Novel bicyclic antibiotics

ABSTRACT

The antibacterial compound of formula I 
     
       
         
         
             
             
         
       
     
     wherein
     X1, X3; X4 and X6, each independently of the others, represents a nitrogen atom or CR2, with the proviso that at least one of X1, X3; X4 and X6 represents a nitrogen atom;   X2 represents C—H, C—(C1-C6alkyl), C—(C1-C6alkoxy), C-halogen, C—COOH;   X5 represents C—H or C—(C1-C6alkyl), C-halogen; A1, A2, A3, R1 and R4 represent various substituents, G represents aryl or heteroaryl, which is unsubstituted or substituted which compounds show good activity against pathogenic bacteria.

The present invention relates to antibacterial compounds of a formula:

wherein X1, X2, X3; X4, X5, X6, and X7, each independently of theothers, represent nitrogen or CR2 wherein at least one of all groups X1,X2, X3; X4, X5, X6, and X7 but not more than two of either X4, X5 and X6or X1, X2, X3 and X7 represent nitrogen andwherein R1 and R2 are selected from hydrogen and certain substituentswhich substituents also include more complex molecular side chains.

Many of such antibacterial compounds are already known in the art. Theseknown compounds have in common that X1 represents CR2 wherein R2represents such a molecular side chain like e.g. correspondingquinolines, quinoxalines or naphthyridines, which are known fromWO2002/072572, WO2004/035569, WO2006/002047, WO2006/014580,WO2006/021448, WO2006/032466, and WO2007/086016.

By way of example, WO2006/021448 discloses antibacterial compounds withthe general structure

whereinX2, X3, X4, X5, X6 and X7 independently represent N or CR2,wherein R2 represents hydrogen or a substituent;SP represents linear two-atomic spacer group like in particular —NHCO—;—CH₂CO—; —COCH₂—, —CH₂SO₂—; —NHSO₂—; —CH₂CH(OH)—; —CH₂CH₂—; —CH(OH)CH₂—;—CONH—; —CH₂N(C₁-C₄ alkyl)-; —CH₂O— or —CH₂S— andR represents a group selected from C6-C8cycloalkylene groups; saturatedand unsaturated 4 to 8-membered heterocyclodiyl with 1, 2 or 3heteroatoms selected from nitrogen and oxygen, which group isunsubstituted or substituted.

The numerous exemplified compounds are said to exhibit a MIC (μg/ml)against at least one of the following microorganisms: Acinetobacterbaumaimii; Enterobacter cloacae; Escherichia coli; Klebsiellapneumoniae; Proteus mirabilis; Pseudomonas aeruginosa; Stenotrophomonasmaltophilia; Staphylococcus aureus; Enterococcus faecalis;Staphylococcus epidermidis; Streptococcus pneumoniae and Enterococcusfaecium of less or equal to 8 μg/ml.

In view of the increasing resistance development of pathogenic bacteriaagainst known antibacterial agents, including multiple resistances,there is an ongoing need to find novel antibacterial substances, inparticular compounds having a different chemical structure.

The present invention relates to such antibacterial compounds of novelchemical structure. In particular, it relates to compounds of formula(I)

whereinX1, X3; X4 and X6, each independently of the others, represents anitrogen atom or CR2, with the proviso that at least one of X1, X3; X4and X6 represents a nitrogen atom;X2 represents C—H, C—(C1-C6alkyl), C—(C1-C6alkoxy), C-halogen, C—COOH;X5 represents C—H or C—(C1-C6alkyl), C-halogen;R1 and R2, independently of one another, represent hydrogen or asubstituent selected from hydroxy, halogen, carboxy, amino,C1-C6alkylamino, di(C1-C6alkyl)amino, mercapto (SH), cyano, nitro,C1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio, C1-C6alkylaminocarbonyloxy,C2-C6alkenyl, C2-C6alkynyl, C5-C6alkylcarbonyloxy,C1-C6alkylsulfonyloxy, C1-C6heteroalkylcarbonyloxy,C5-C6heterocyclylcarbonyloxy, C1-C6heteroalkyl, C1-C6heteroalkoxy,wherein heteroalkyl, heteroalkoxy groups or heterocyclyl comprise 1, 2or 3 heteroatoms selected from nitrogen, oxygen and sulphur, in whichsubstituents the alkyl moieties are unsubstituted or further substitutedby halogeno, cyano, hydroxy, C1-C4alkoxy, C1-C4alkylcarbonyl,C1-C4alkoxycarbonyl, unsubstituted or substituted phenoxy orphenylcarbonyl, unsubstituted or substituted C5-C6heterocyclyl orcarboxy;A1 represents a divalent group of one of the formulae—O—(CH₂)_(m)—(CH₂)—, —S—(CH₂)_(m)—(CH₂)— or —(C═O)O—(CH₂)_(m)—(CH₂)—,wherein the (CH₂)_(m) moiety is optionally substituted by C1-C4alkyl,C2-C4alkenyl, C3-C6cycloalkyl, C3-C6cycloalkylmethyl, morpholinomethyl,halogen, carboxy, hydroxy, C1-C4alkoxy;C1-C4alkoxyC1-C4alkyl, C1-C4alkoxy(C1-C4alkylenoxy)C1-C4alkyl,benzyloxyC1-C4alkyl, amino, mono- or di-(C1-C4alkyl)amino or acylamino,in which substituents the alkyl moieties can be further substituted by 1or more fluoro atomsm is 0, 1 or 2, provided that the number of atoms in the direct chainbetween the two terminal valencies of A1 is at least 3,which group A1 is linked to A2 via the terminal (CH₂)-moiety;A2 is a group selected from C3-C8cycloalkylene; saturated andunsaturated 4 to 8-membered heterocyclodiyl with 1, 2 or 3 heteroatomsselected from nitrogen, oxygen and sulphur, which group A2 isunsubstituted or substituted;R4 represents hydrogen or C1-C4alkyl;A3 represents C1-C4alkylene, C2-C4alkenylene, >C═O, —C(O)C1-C3alkylene-,—C(═O)NH—, or a group selected from —C₂H₄NH—, —C₂H₄O—, and —C₂H₄S— beinglinked to the adjacent NR4-group via the carbon atom; andG represents aryl or heteroaryl, which is unsubstituted or substitutedandn is 0, 1 or 2;or a pharmaceutically acceptable salt, a hydrate or solvate thereof.

The compounds of the invention show good activity against pathogenicbacteria, in particular against at least one of the followingGram-positive pathogenic bacteria like staphylococci, streptococci andGram-negative bacteria such as for example Escherichia coli, as shown inthe Examples. Furthermore they are active against enterococci, andHaetnophilus influenzae.

The antibacterial activity found is particularly surprising because ithas been found that the compounds of WO2006/021448 loose theirantibacterial activity when the side chain is shifted from the positiondisclosed in WO2006/021448 to that of the present invention as shown inthe following table.

Comparison of the C4 and C3 position of the methoxyquinoline using thesame side chain

MIC (mg/L) C4 postion according to C3 position according toWO2006/021448 present invention  

         

     

S. aureus 0.5 1 >32 >32 ATCC29213 S. pneumoniae 0.5 2 32 32 ATCC49619 E.coli 16 1 >32 >32 UB1005

The expression “C1-C6alkyl” preferably refers to saturated,straight-chain or branched hydrocarbon groups having from 1 to 6 carbonatoms like, for example methyl, ethyl, propyl, iso-propyl, n-butyl,iso-butyl, tert-butyl, n-pentyl, n-hexyl or 2,2-dimethylbutyl. C1-C4alkyl is generally preferred. In composed expressions, like e.g.C1-C6alkoxy, C1-C6alkylamino or di(C1-C6alkyl)amino, aralkyl orheteroaralkyl or the like“C1-C6alkyl” is understood in the same way.Alkyl groups may also be further substituted by carboxy, amino, mono- ordi(C1-C4alkyl)amino, halogeno, e.g. by fluorine, chlorine, bromine oriodine, cyano, hydroxy, mercapto, C1-C4alkoxy, C1-C4alkylcarbonyl,C1-C4alkoxycarbonyl, unsubstituted or substituted phenoxy orphenylcarbonyl, unsubstituted or substituted C5-C6heterocyclyl or by ═O,═S, ═NH or NO₂ groups and the like, in which alkyl substituents theC1-C4alkyl or C1-C4alkoxy groups are unsubstituted.

The expressions “C2-C6alkenyl” and “C2-C6alkynyl” preferably refer to atleast partially unsaturated, straight-chain or branched hydrocarbongroups that contain from 2 to 6 carbon atoms, preferably from 2 to 4carbon atoms like, for example, ethenyl, allyl, propargyl, isoprenyl orhex-2-enyl group. Preferably, alkenyl groups have one or two (especiallyone) double bond(s) and alkynyl groups have one or two (especially one)triple bond(s). Groups having one double and one triple bond are alsocovered like e.g. pent-3-en-1-yne. The alkenyl and alkynyl groups mayalso be further substituted by carboxy, amino, mono- ordi(C1-C4alkyl)amino, halogeno, e.g. by fluorine, chlorine, bromine oriodine, cyano, hydroxy, mercapto, C1-C4alkoxy, C1-C4alkylcarbonyl,C1-C4alkoxycarbonyl, unsubstituted or substituted phenoxy orphenylcarbonyl, unsubstituted or substituted C5-C6heterocyclyl or by ═O,═S, ═NH or NO₂ groups and the like, in which alkyl substituents theC1-C4alkyl or C1-C4alkoxy groups are unsubstituted.

The expression “C3-C6heteroalkyl” preferably refers to an alkyl, alkenylor alkynyl group (for example heteroalkenyl, heteroalkynyl) in which oneor more (preferably 1, 2 or 3) carbon atoms have been replaced eachindependently of the others by an oxygen, nitrogen, silicon or sulphuratom, preferably an oxygen, sulphur or nitrogen atom. Specific examplesof heteroalkyl groups are methoxymethyl, ethoxymethyl, methoxyethyl,methylaminomethyl, ethylaminomethyl, diisopropyl-aminoethyl, enol ether,dimethylaminomethyl, dimethylaminoethyl. The alkyl part(s) of“C3-C6heteroalkyl” can be further substituted as defined for C1-C6alkyl.

The expression “C3-C8cycloalkylene” preferably refers to a bivalentsaturated or partially unsaturated (for example a cyclic group havingone, two or more double bonds, such as a cycloalkenylene group), cyclicgroup containing from 3 to 8 carbon atoms, especially 3, 4, 5, 6 or 7,preferably 5 or 6 ring carbon atoms. For the purposes of the presentinvention the expression cycloalkylene refers furthermore to groups inwhich one or more hydrogen atoms have been replaced each independentlyof the others by carboxy, amino, mono- or di(C1-C4alkyl)amino, halogeno,e.g. by fluorine, chlorine, bromine or iodine, cyano, hydroxy, mercapto,C1-C4alkoxy, C1-C4alkylcarbonyl, C1-C4alkoxycarbonyl, unsubstituted orsubstituted phenoxy or phenylcarbonyl, unsubstituted or substitutedC5-C6heterocyclyl or by ═O, ═S, ═NH or NO₂ groups and the like, in whichalkyl substituents the C1-C4alkyl or C1-C4alkoxy groups areunsubstituted, thus, for example, to bivalent residues of cyclic ketonessuch as, for example, cyclohexanone, 2-cyclohexenone or cyclopentanone.Further specific examples of cycloalkylene groups are cyclobutylene,cyclopentylene, cyclohexylene, cyclopentenylene and cyclohexadienylene.

The expression “heterocyclodiyl” as used herein preferably refers to asaturated or unsaturated bivalent 4 to 8-membered cyclic group asdefined above in connection with the definition of cycloalkylene(including divalent heteroaromatic groups), in which one or more(preferably 1, 2 or 3) ring carbon atoms have been replaced eachindependently of the other by an oxygen, nitrogen, silicon, or sulphuratom, preferably by an oxygen, sulphur or most preferably nitrogen atom.The expression heterocyclodiyl refers furthermore to groups in which oneor more hydrogen atoms have been replaced each independently of theothers by carboxy, amino, mono- or di(C1-C4alkyl)amino, halogeno, e.g.by fluorine, chlorine, bromine or iodine, cyano, hydroxy, mercapto,C1-C4alkoxy, C1-C4alkylcarbonyl, C1-C4alkoxycarbonyl, unsubstituted orsubstituted phenoxy or phenylcarbonyl, unsubstituted or substitutedC5-C6heterocyclyl or by ═O, ═S, ═NH or NO₂ groups and the like, in whichalkyl substituents the C1-C4alkyl or C1-C4alkoxy groups areunsubstituted. Preferred substituents of heterocyclodiyl groups, inparticular of A2 in the meaning “heterocyclodiyl” are hydroxy,C1-C4alkyl and carboxy. Suitable examples of heterocyclodiyl groupsinclude piperidin-diyl, piperazin-diyl, morpholin-diyl, pyrrolidin-diyl,tetrahydro-thiophenyl-diyl, tetrahydropyran-diyl, tetrahydrofuran-diylor 2-pyrazolin-diyl. Particularly preferred are saturated or unsaturated4 to 6-membered heterocyclodiyl groups with one or two nitrogen atoms asthe heteroatom(s), in particular saturated 4 to 6-memberedheterocyclodiyl with one nitrogen atom as the heteroatom.

The expression “aryl” as used herein preferably refers to an aromaticgroup that contains one or more rings and from 6 to 14 ring carbonatoms, preferably from 6 to 10 (especially 6) ring carbon atoms. Theexpression aryl preferably refers furthermore to such groups in whichone or more hydrogen atoms have been replaced each independently of theothers by alkyl, fluorine, chlorine, bromine or iodine atoms or bycarboxy, alkoxy, mono- or di(C1-C4alkyl)amino, OH, NH₂, cyano or NO₂groups. Examples are phenyl, 4-methyl-phenyl, 4-tert-butyl-phenyl;3-fluoro-4-methyl-phenyl, 3-fluoro-4-(trifluoromethyl)-phenyl; naphthyl,biphenyl, 2-fluorophenyl, anilinyl, 3-nitro-phenyl or 4-hydroxyphenyl.

The expression “heteroaryl” as used herein preferably refers to anaromatic group that contains one or more rings and from 5 to 14 ringatoms, preferably from 5 to 10 (especially 5, 6, 8, 9 or 10) ring atoms,and contains one or more (preferably 1, 2, 3 or 4) oxygen, nitrogen orsulphur ring atoms, preferably oxygen, sulfur or nitrogen atoms. Theexpression heteroaryl preferably refers furthermore to groups in whichone or more hydrogen atoms have been replaced each independently of theothers by fluorine, chlorine, bromine or iodine atoms or by carboxy,alkyl, alkoxy, mono- or di(C1-C4alkyl)amino, OH, mercapto, NH₂, cyano,NO₂ or unsubstituted heteroaryl groups. Examples are pyridyl,imidazolyl, thiophenyl, thieno[3,2-b]thiophenyl, benzo[b]thiophenyl,furanyl, benzofuranyl, imidazolyl, benzimidazolyl, pyrrolyl, indolyl,oxazolyl, isoxazolyl, indazolyl, indolyl, pyridazinyl, quinolinyl,purinyl, carbazolyl, acridinyl, pyrimidyl, pyrazolyl and isoquinolinylgroups.

Further rings can be fused to the aryl and heteroaryl groups as definedabove, in particular further cycloalkane and/or in particularheterocycloalkane groups.

For the purposes of this invention the term “cycloalkane” preferablyrefers to a saturated or partially unsaturated cyclic group whichcontains one or more, e.g. one or two rings and from 3 to 14 ring carbonatoms, preferably from 3 to 10, most preferably 5 or 6 ring carbonatoms. The term cycloalkane preferably refers furthermore to such groupsin which one or more hydrogen atoms have been replaced eachindependently of the others by fluorine, chlorine, bromine or iodineatoms or by carboxy, alkyl, alkoxy, mono- or di(C1-C4alkyl)amino or byOH, ═O, SH, ═S, NH₂, ═NH, cyano or NO₂ groups, thus, for example, cyclicketones such as, for example, cyclohexanone or cyclopentanone. Furtherspecific examples of cycloalkane groups are a cyclopropane, cyclobutane,cyclopentane, cyclohexane, cyclopentene, cyclohexadiene.

The expression “heterocycloalkane” as used herein preferably refers tocycloalkane groups as defined above in which one or more, preferably 1,2 or 3 ring carbon atoms have been replaced each independently of theothers by an oxygen, nitrogen, silicon or sulphur atom, preferably anoxygen, sulphur or nitrogen atom. A heterocycloalkane group haspreferably 1 or 2 ring(s) containing from 3 to 10, most preferably 5 or6 ring atoms. The expression heterocycloalkane preferably refersfurthermore to groups in which one or more hydrogen atoms have beenreplaced each independently of the others by fluorine, chlorine, bromineor iodine atoms or by carboxy, alkyl alkoxy, mono- ordi(C1-C4alkyl)amino or by OH, ═O, SH, ═S, NH₂, ═NH, cyano or NO₂ groups.Examples are a piperidine, piperazine, morpholine, pyrrolidine,thiomorpholine, tetrahydrothiophene, [1,4]dioxane, tetrahydropyrane,tetrahydrofurane or pyrazoline and also lactams, lactones, cyclic imidesand cyclic anhydrides, like e.g., morpholin-3-one orthiomorpholin-3-one.

The expression halogen refers to fluorine, chlorine bromine and iodine.

Certain compounds of formula (I) may contain one, two or more centres ofchirality. The present invention therefore includes both all pureenantiomers and all pure diastereoisomers and also mixtures thereof inany mixing ratio. The present invention moreover also includes allcis/trans-isomers of the compounds of the general formula (I) andmixtures thereof. The present invention moreover includes all tautomericforms of the compounds of formula (I).

Preferred are compounds of formula (I) wherein either X3 alonerepresents a nitrogen atom (corresponding quinoline derivatives) or X3and X1 represent a nitrogen atom (corresponding quinoxaline derivatives)or X3 and X6 represent a nitrogen atom (corresponding[1,5]-naphthyridine derivatives). Especially preferred are the compoundswherein X3 and X1 or X3 and X6 represent nitrogen. Those groups X whichdo not represent a nitrogen atom are preferably a CH group.

Particularly preferred are furthermore the compounds according to theinvention, wherein R1 is selected from halogen and C1-C6alkoxy,preferably C1-C4alkoxy, in particular from fluoro and methoxy.

Another preferred group of the compounds according to the presentinvention are those, wherein A2 represents a group selected fromC5-C6cycloalkylene and saturated or unsaturated 4 to 6-memberedheterocyclodiyl with one or two nitrogen atoms as the heteroatom(s), inparticular unsubstituted C5-C6cycloalkylene and saturated 4 to6-membered heterocyclodiyl with one nitrogen atom as the heteroatom, inparticular the compounds of formula (I) wherein

A2 is selected from:

wherein* indicates the bond to the (CH₂)_(n) group in formula (I).

The group G in formula (I) represents preferably a C6-C10aryl groupwhich is unsubstituted or further substituted by one or more halogenatoms, in particular chloro or fluoro, and/or straight-chain or branchedC1-C4alkyl groups which may optionally be further substituted by fluoro,like e.g. trifluoromethyl; or a phenyl group or a 5- or 6-memberedheteroaryl group comprising heteroatoms selected from oxygen, sulphur ornitrogen, which phenyl group or 5- or 6-membered heteroaryl group areunsubstituted or substituted by one or more halogen atoms, in particularchloro or fluoro, and/or straight-chain or branched C1-C4alkyl groupswhich may optionally be further substituted by fluoro, like e.g.trifluoromethyl, or by an unsubstituted 5- or 6-membered heteroarylgroup, to which phenyl group or 5- or 6-membered heteroaryl groupfurther optionally a benzene ring or a 5- or 6-membered heteroarenering, which is unsubstituted or substituted by one or more halogenatoms, in particular chloro or fluoro, and/or straight-chain or branchedC1-C4alkyl groups which may optionally be further substituted by fluoro,like e.g. trifluoromethyl, or a heterocycloalkane ring may be fusedwhich comprises five to six ring atoms and heteroatoms selected fromoxygen, sulphur or nitrogen and optionally a ═O group as substituent.

Particularly preferred as group G are the following groups:

Particularly preferred in view of antibacterial activity are thecompounds of formula (I) wherein A1 represents —O—(CH₂)_(m)—(CH₂)— or,even more preferred, —S—(CH₂)_(m)—(CH₂)—.

Especially preferred are these compounds when m is 1.

The compounds of formula (I) wherein n is 0 or 1 are yet a furtherpreferred group of the compounds of the present invention.

Further specific embodiments of the present invention are:

-   -   compounds according to the invention, wherein X3 and X1 are        nitrogen;    -   compounds according to the invention, wherein R2 is selected        from hydrogen, hydroxy, halogen, C1-C6alkyl, C1-C6alkoxy,        carboxy;    -   compounds according to the invention, wherein A2 is        unsubstituted or substituted with a group selected from hydroxy,        C1-C4alkyl and carboxy; and    -   compounds according to the invention, wherein (CH₂)_(m) is        unsubstituted or substituted with groups selected from        C1-C6alkyl and C1-C6alkenyl.

All aforementioned specific embodiments or preferences can also becombined in any possible manner, and all these combinations areconsidered to be further embodiments of the present invention.

Examples of pharmacologically acceptable salts of the compounds offormula (I) are salts of physiologically acceptable mineral acids, suchas hydrochloric acid, sulphuric acid and phosphoric acid, or salts oforganic acids, such as methane-sulphonic acid, p-toluenesulphonic acid,lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinicacid, fumaric acid, maleic acid and salicylic acid. Further examples ofpharmacologically acceptable salts of the compounds of formula (I) arealkali metal and alkaline earth metal salts such as, for example,sodium, potassium, lithium, calcium or magnesium salts, ammonium saltsor salts of organic bases such as, for example, methylamine,dimethylamine, triethylamine, piperidine, ethylenediamine, lysine,choline hydroxide, meglumine, morpholine or arginine salts.

The compounds of formula (I) may also be solvated, especially hydrated.Solvation and hydration may take place, for example, during thepreparation process.

The compounds according to the present invention, pharmaceuticallyacceptable salts, solvates or hydrates thereof can be prepared e.g. byone of the processes (a), (b) or (c) described below; followed, ifnecessary, by:

removing any protecting groups;forming a pharmaceutically acceptable salt;forming a pharmaceutically acceptable solvate or hydrate.

Process (a):

A compound of the formula II

is reacted with a compound of formula (III)

G-A3b-L0  (III):

in which formulaeX1, X2, X3, X4, X5, X6, R1, A2, G, R4, m and n are as in formula I,A represents a group selected from —O—; —S—; and —C(═O)O—, which—C(═O)O— group is linked to the adjacent (CH₂)_(m) group via the oxygenatom,L0 is selected from —CH₂Y, —CHO, —COOH and —COCl,Y is a leaving group like methylsulfonyl, tolylsulfonyl,trifluoromethylsulfonyl or halogen,A3b is absent or represents C1-C3alkylene, C1-C3alkenylene, or a groupselected from —CH₂NH—, —CH₂O—, and —CH₂S—, said group being linked to Gvia the nitrogen, oxygen or sulfur atom,

In certain cases L0 may require appropriate activation to allow areaction of compounds of formulae II and III as described in more detailbelow.

Process (b):

A compound of the formula IV

is reacted with a compound of formula V

in which formulaeX1, X2, X3, X4, X5, X6, R1, A2, R4, m and n are as in formula I,L1 is C(═O)OH or a corresponding acid halide or otherwise activated acylderivative, anhydride or mixed anhydride, OH, SH, Br, Cl or a groupOSO₂R in which R is CH₃, CF₃, or tolyl, andL2 is a halogen atom, SH, OH or a group OSO₂R in which R is CH₃, CF₃, ortolyl, andL1 and L2 are selected such that the reaction results in the formationof a compound of formula VIII

wherein A is as defined above,E is -A3-G (A3 and G being as defined in formula I) or an aminoprotecting group, such as allyloxycarbonyl, benzyloxycarbonyl,9-fluorenylmethylcarbonyl tert-butoxycarbonyl or benzyl, andwhen E is a protecting group, said protecting group is removed and thedeprotected intermediate is reacted with a compound of formula III

G-A3b-L0  (III):

wherein G, A3b and L0 are as defined above.

Again L0 may, in certain cases, require appropriate activation to allowconnection of the deprotected intermediate and the compound of formula(III).

Process (c):

A compound of formula VI

is reacted with a compound of formula VII

wherein in formulae (VI) and (VII)X1, X2, X3, X4, X5, X6, R1, R4, m and n are as in formula I,A represents a group selected from —O—; —S—; and —C(═O)O—, the —C(═O)O—group being linked to the adjacent (CH₂)_(m) group via the oxygen atom,A2 is an unsubstituted or substituted, saturated or unsaturated 4 to8-membered heterocyclodiyl group with 1, 2 or 3 heteroatoms selectedfrom nitrogen, oxygen and sulphur, at least one of which heteroatoms isnitrogen atom andH^([-N]) represents a hydrogen atom bound to bound to a nitrogen ringatom of A2, L3 is —CHO, andE is an amino protecting group or a group of formula -A3-G, whereinA3 and G have the same meaning as in formula I, and whereinwhen E is a protecting group, said protecting group is removed and thedeprotected intermediate is reacted with a compound of formula III

G-A3b-L0  (III):

wherein G, A3 and L0 are as defined aboveAgain L0 may, in certain cases, require appropriate activation to allowconnection of the deprotected intermediate and the compound of formula(III).

The necessary starting materials for the synthetic methods as describedherein, if not commercially available, may be made by procedures whichare described in the scientific literature, or could be made fromcommercially available compounds using adaptations of processes reportedin the scientific literature. The reader is further referred to AdvancedOrganic Chemistry, 5^(th) Edition, by J. March and M. Smith, publishedby John Wiley & Sons, 2001, for general guidance on reaction conditionsand reagents.

Furthermore in some of the reactions mentioned herein it may benecessary or desirable to protect any sensitive groups in compounds.Conventional protecting groups may be used in accordance with standardpractice (for illustration see Protective Groups in Organic Synthesis,3^(rd) Edition, by T. W. Greene and P. G. M. Wuts, published by JohnWiley & Sons, 1999).

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the art, or theymay be removed during a later reaction step or work-up.

In Scheme 1, PG1 is a protecting group (such as allyloxycarbonyl(Alloc), benzyloxycarbonyl, 9-fluorenylmethylcarbonyl (Fmoc),tert-butoxycarbonyl (Boc) or benzyl), L1 and L2 are halogen, inparticular Br, Cl, or OH, and the other symbols have the same meaningsas previously described.

Compounds of formula V-1 are usually obtained by reacting thecorresponding free amine with allyl, fluorenylmethyl or benzylchloroformate or with di tert-butyl dicarbonate in presence of a basesuch as sodium hydroxide, sodium hydrogencarbonate, triethylamine,4-dimethylaminopyridine or imidazole. They can also be protected asN-benzyl derivatives by reaction with benzyl bromide or chloride inpresence of a base such as sodium carbonate or triethylamine.Alternatively, N-benzyl derivatives can be obtained through reductiveamination in presence of benzaldehyde. Further strategies to introduceother amine protecting groups have been described in Protective Groupsin Organic Synthesis, 3^(rd) Edition, by T. W. Greene and P. G. M. Wuts,published by John Wiley & Sons, 1999.

Compounds of formula VIII-1 (Scheme 1) can be obtained from compounds offormula V-1 wherein L2 is —OH via a Mitsunobu coupling (as reviewed inO. Mitsunobu, Synthesis 1981, 1) with compounds of formula IV-1 forwhich L1 is a hydroxy group. The reaction is for example performed inthe presence of diethyl or diisopropyl azodicarboxylate andtriphenylphosphine, in a wide range of solvents such asN,N-dimethylformamide, tetrahydrofuran, 1,2-dimethoxyethane ordichloromethane and within a wide range of temperatures (between −20° C.and 60° C.). The reaction might also be performed usingpolymer-supported triphenylphosphine.

An alternative route to form compounds of formula VIII-1 consists ofreacting compounds of formula V-1 wherein L2 is —OH with compounds offormula IV-1 for which L1 is a hydroxy group, which needs to beactivated prior to the reaction as described below or a halogen atom inpresence of an inorganic base such as sodium hydride or the like in asolvent such as dichloromethane or N,N-dimethylformamide at atemperature ranging between −20° C. and 80° C. Activation of the hydroxygroup of compounds of formula V-1 wherein L1 is —OH as for example amesylate, a tosylate or a triflate can be achieved by reacting thecompound of formula V-1 wherein L1 is —OH with methanesulfonyl chlorideor methanesulfonic anhydride, p-toluenesulfonyl chloride,trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride,respectively, in presence of a base such as triethylamine or the like ina dry aprotic solvent such as pyridine, acetonitrile, tetrahydrofuran ordichloromethane between −30° C. and 60° C.

Finally, compounds of formula VIII-1 can be generated by reactingcompound of formula IV-1 wherein L1 is a hydroxy group with a compoundof formula V-1 wherein L2 is a halogen atom or a hydroxyl group whichneeds to be activated prior to the reaction as for example a mesylate,tosylate or triflate as described above. The coupling is performed inpresence of an inorganic base such as sodium hydride in a solvent suchas dichloromethane or N,N-dimethylformamide at a temperature rangingbetween −20° C. and 80° C.

Removal of the protecting group PG1 in compounds of formula VIII-1 iscarried out under standard conditions to generate compounds of formulaII-1. For example the benzyl carbamates are deprotected byhydrogenolysis over a noble catalyst (e.g. palladium on activatedcarbon). The Boc group is removed under acidic conditions such ashydrochloric acid in an organic solvent such as ethyl acetate, ortrifluoroacetic acid neat or diluted in a solvent such asdichloromethane. The Alloc group is removed in presence of a palladiumsalt such as palladium acetate ortetrakis(triphenylphosphine)palladium(0) and an allyl cation scavengersuch as morpholine, pyrrolidine, dimedone or tributylstannane between 0°C. and 70° C. in a solvent such as tetrahydrofuran. The N-benzylprotected amines are deprotected by hydrogenolysis over a noble catalyst(e.g. palladium dihydroxide). The Fmoc protecting group is removed undermild basic conditions such as diluted morpholine or piperidine inN,N-dimethylformamide. Further general methods to remove amineprotecting groups have been described in Protective Groups in OrganicSynthesis, 3^(rd) Edition, by T. W. Greene and P. G. M. Wuts, publishedby John Wiley & Sons, 1999.

Compounds of formula I-1 wherein A3 is CH₂ can be obtained fromintermediate II-1 (Scheme 1) by reaction with a compound of formula IIIwherein L0 is —CHO either in the presence of or followed by a reactionwith a suitable reducing agent. The reaction between the amine and thealdehyde to form an intermediate imine is conducted in a solvent systemallowing the removal of the formed water through physical or chemicalmeans (e.g. distillation of the solvent-water azeotrope or presence ofdrying agents such as molecular sieves, magnesium sulfate or sodiumsulfate). Such solvents are typically toluene, n-hexane,tetrahydrofuran, dichloromethane, N,N-dimethylformamide,N,N-dimethylacetamide, acetonitrile, 1,2-dichloroethane or mixture ofsolvents such as methanol:1,2-dichloroethane. The reaction can becatalyzed by traces of acid (usually acetic acid). The imine is reducedsubsequently or simultaneously with a suitable reagent such as sodiumborohydride, sodium triacetoxyborohydride or sodium cyanoborohydride (R.O. and M. K. Hutchins, Comprehensive Organic Synthesis, B. M. Trost, I.Fleming, Eds; Pergamon Press: New York (1991), vol. 8, p. 25-78). Thereaction is preferably carried out between 0° C. and 60° C.

Compounds of formula I-1 wherein A3 is >C(═O) can be obtained fromintermediate II-1 (Scheme 1) through reaction with a carboxylic acidderivative III (L0=COOH), in the presence of an activating agent such asN,N′-dicyclohexylcarbodiimide orN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, with theoptional addition of 1-hydroxybenzotriazole. Other suitable couplingagents may be utilized such as,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline,carbonyldiimidazole or diethylphosphorylcyanide. Optionally, a base liketriethylamine, N,N-diisopropylethylamine or pyridine can be added toperform the coupling. The peptidic coupling is conducted at atemperature comprised between −20° C. and 80° C., in an inert solvent,preferably a dry aprotic solvent like dichloromethane, acetonitrile orN,N-dimethylformamide and chloroform. Alternatively, the carboxylic acidcan be activated by conversion into its corresponding acid chloride orits corresponding activated ester, such as the N-hydroxysuccinimidylester (Org. Process Res. & Dev., 2002, 863) or the benzothiazolylthioester (J. Antibiotics, 2000, 1071). The generated activated entitycan react at a temperature comprised between −20° C. and 80° C. withcompound of formula II-1 in an aprotic solvent like dichloromethane,chloroform, acetonitrile, N,N-dimethylformamide and tetrahydrofuran togenerate compound of formula I-1. Optionally, a base like triethylamine,N,N-diisopropylethylamine, pyridine, sodium hydroxide, sodium carbonate,potassium carbonate can be added to perform the coupling.

Alternatively, compounds of formula I-1 wherein A3 is —CH₂— can beobtained from intermediate II-1 by reaction with a compound of formulaIII wherein L0 is —CH₂Y and Y is a leaving group like methylsulfonyl,tolylsulfonyl, trifluoromethylsulfonyl or halogen at a temperaturebetween −20° C. and 100° C. in a dry aprotic solvent likedichloromethane, acetonitrile, N,N-dimethylformamide or tetrahydrofuranwithout or with a base such as potassium carbonate orN,N-diisopropylethylamine.

In Scheme 1, coupling of compounds of general formulae IV-1 and V-1,followed by a deprotection step and finally introduction of the A3-Gsubstituent allowed the generation of compounds of formula I-1.Alternatively, the protecting group PG1 of compounds of formula V-1 canbe removed according to the methods described above and the product ofthis reaction can then be reacted with one of the compounds of formulaIII as defined above. Subsequently, these intermediates are convertedinto compounds of formula I-1 following the methods described above forthe synthesis of compounds of formula VIII-1.

In Scheme 2, L1 is a carboxylic acid C(O)—OH or its corresponding acidhalide or other activated acyl derivatives, anhydride or mixedanhydride. All the other symbols have the same meanings as in formula Ior in Scheme 1.

The reaction between compounds of formulae IV-2 wherein L1 is COOH andV-2 to generate compounds of formula I-2 is performed with the additionof a coupling agent such as N,N′-dicyclohexylcarbodiimide or the like,and optionally with the addition of 4-dimethylaminopyridine, imidazoleor the like. The reaction between compounds of formula IV-2 wherein L1is an acid halide, or any other activated acyl derivative and V-2 togenerate compounds of formula I-2 is performed in the presence of a basesuch as triethylamine or sodium hydride and optionally4-dimethylaminopyridine. The acylation is conducted at a temperaturecomprised between −20° C. and 60° C., in an inert solvent, preferably adry aprotic solvent like dichloromethane, acetonitrile,N,N-dimethylformamide or chloroform.

Alternatively, compounds of formula I-2 can be generated by firstcoupling compounds of formulae IV-2 and V-3 according to the methodsdescribed above to generate the intermediate VIII-2 and subsequentremoval of the protecting group PG1 and introduction of the substituentA3-G following procedures previously described for Scheme 1.

In Scheme 3, L1 and L2 are SH, Br, Cl or the group OSO₂R in which R isCH₃, CF₃, or tolyl and all the other symbols have the same meanings asin formula I or in Scheme 1.

In the case where A2 in compound VIII-3 is a saturated or unsaturated 4to 8-membered heterocyclodiyl group, which is linked to the—CH₂—(CH₂)_(m)—S— group via a ring nitrogen atom, the compounds offormula VIII-3 can be obtained via reductive amination between VI-1 andVII-1 following procedures previously described in conjunction withScheme 1 for the preparation of compounds of formula I-1 wherein A3 isCH₂ by reaction of an intermediate II-1 with a compound of formula IIIwherein L0 is —CHO.

Alternatively, compounds of formula VIII-3 can be obtained by reactingcompounds of formula IV-3 for which L1 is SH with compounds of formulaV-4 for which L2 is Br, Cl or the group OSO₂R in which R is CH₃, CF₃, ortolyl in presence of a base such as sodium hydroxide, sodium hydride,sodium carbonate, potassium hydroxide, potassium carbonate,triethylamine in a solvent such as acetone, acetonitrile, ethanol,isopropanol or N,N-dimethylformamide at a temperature ranging between 0°C. and 120° C. In this procedure, the mesylate, tosylate or triflatederivatives are generated from the corresponding alcohol followingprocedures previously described for Scheme 1.

Alternatively, compounds of formula VIII-3 can be obtained by reactingcompounds of formula IV-3 for which L1 is Br, Cl or the group OSO₂R inwhich R is CH₃, CF₃, or tolyl with compounds of formula V-4 where L2 isSH. In that case, the reaction can be performed in presence of apalladium salt such as palladium acetate ortetrakis(triphenylphosphine)palladium(0) with the optional addition of abase such as sodium tert-butylate in a solvent such as toluene,N,N-dimethylformamide, dioxane at a temperature ranging from 0° C. and150° C.

The intermediates VIII-3 are further transformed into compounds offormula I-3 using synthetic routes previously described for Scheme 1.

Alternatively, the protecting group PG1 of compounds of formula V-4 canbe removed and the product of this reaction can then be reacted with acompound of formula III according to the methods described above.Subsequently, these intermediates are reacted with compounds of formulaIV-3 to give the compounds of formula I-3 following the methodsdescribed above for the synthesis of compounds of formula VIII-1.

Starting Materials:

Unless otherwise stated the required starting compounds of formulae IVand VI are commercially available or prepared following literatureprocedures. For example, quinoxalines (IV; X2=X4=X5=X6=CH, X1=X3=N) maybe prepared from the corresponding anilines following standard routes asdescribed in J. Med. Chem., 2001, 44, 1758, J. Chem. Soc., 1949, 1271and PCT Pub. No. WO2004/014871; [1,5]-naphthyridines (IV;X1=X2=X4=X5=CH, X3=X6=N) and quinolines (IV; X3=N, X1=X2=X4-X5-X6-CH)can be prepared from the corresponding aminopyridines or anilines,respectively, by applying standard procedures as described in J. Med.Chem., 2002, 45, 3130 and the patent literature, such as PCT Pub. No.WO2004/058144, WO95/00511, U.S. Pat. No. 5,442,065, EP0293071.

Unless otherwise stated the required starting derivatives of formulae Vand VII are prepared following or adapting synthetic proceduresdescribed in the patent literature, such as PCT Pub. No. WO2006/099884and WO2006/004949.

Unless otherwise stated compounds of formula III-1, III-2 and III-3 arecommercially available or may be obtained by procedures described in thepatent literature, such as PCT Pub. No. WO2007/093507, WO2007/052843,WO2006/105289, WO2006/038734, WO2006/021448, WO2004/058144,WO2004/002992, WO02/34754.

When an optically active form of a compound of the invention isrequired, it may be obtained by carrying out one of the above proceduresusing a pure enantiomer or diastereomer as a starting material, or byresolution of a mixture of the enantiomers or diastereomers of the finalproduct or intermediate using a standard procedure. The resolution ofenantiomers may be achieved by chromatography on a chiral stationaryphase, such as REGIS PIRKLE COVALENT (R-R) WHELK-02, 10 μm, 100 Å,250×21.1 mm column. Alternatively, resolution of stereoisomers may beobtained by preparation and selective crystallization of adiastereomeric salt of a chiral intermediate or chiral product with achiral acid, such as camphorsulfonic acid. Alternatively a method ofstereoselective synthesis may be employed, for example by using a chiralvariant of a protecting group, a chiral catalyst or a chiral reagentwhere appropriate in the reaction sequence.

Enzymatic techniques may also be useful for the preparation of opticallyactive compounds and/or intermediates.

Further aspects of the invention include

-   -   pharmaceutical compositions comprising a compound of formula (I)        or a pharmaceutically acceptable salt, a hydrate or solvate        thereof and a pharmaceutically acceptable carrier;    -   the compounds of formula (I) or a pharmaceutically acceptable        salt, a hydrate or solvate thereof for use as a medicament, in        particular a medicament for the treatment of bacterial        infections; and    -   the use of a compound of formula (I) or a pharmaceutically        acceptable salt, a hydrate or solvate thereof for the        preparation of medicaments for the treatment of infectious        diseases caused by bacteria.

The compounds of number 1, 2, 3, 4, 5, 6, 7, 8, 9, 14, 15, 16, 17, 18,19, 20, 28, 29, 30, 31, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52, 53, 54, 55 and 56 indicated in Table 1 below areparticularly advantageous for the treatment of infections byStaphylococcus aureus and/or Staphylococcus epidermidis and exhibit aMIC for said strains of generally ≦2 mg/L.

The compounds of number 2, 5, 9, 35, 36, 37, 38, 39, 40, 41, 42, 43, 45,46, 47, 48, 49, 50, 52, 53 and 55 indicated in Table 1 below areparticularly advantageous for the treatment of infections byStaphylococcus aureus and/or Staphylococcus epidermidis and/orStreptococcus pneumoniae and exhibit a MIC for said strains of generally≦2 mg/L.

The compounds of number 9, 36, 37, 40, 44, 45, 46, 48, 49, 50, 51, 53and 54 indicated in Table 1 below are particularly advantageous for thetreatment of infections by Staphylococcus aureus and/or Staphylococcusepidermidis and/or Streptococcus pneumoniae and/or Escherichia coli andexhibit a MIC for said strains of generally ≦4 mg/L, in most case ofless than 2 mg/L.

Furthermore, the compounds selected from the compounds of number 58, 62,63, 67, 71, 73, 76, 78, 79, 80, 81, 94, 95, 101, 102, 103, 104, 105,113, 114, and 122 are particularly useful for the treatment ofinfections by Staphylococcus aureus and/or Staphylococcus epidermidis,the compounds of number 67, 78, 81, 95, 102, 103, 104, 105 and 122 forthe treatment of infections by Staphylococcus aureus and/orStaphylococcus epidermidis and/or Streptococcus pneumoniae and thecompounds of number 102 and 103 for use as a medicament againstinfections by Staphylococcus aureus and/or Staphylococcus epidermidisand/or Streptococcus pneumoniae and/or Escherichia coli.

In general, compounds of formula (I) are administered eitherindividually, or optionally also in combination with another desiredtherapeutic agent, using the known and acceptable methods. Suchtherapeutically useful agents may be administered, for example, by oneof the following routes: orally, for example in the form of dragees,coated tablets, pills, semi-solid substances, soft or hard capsules,solutions, emulsions or suspensions; parenterally, for example in theform of an injectable solution; rectally in the form of suppositories;by inhalation, for example in the form of a powder formulation or aspray; transdermally or intranasally.

For the preparation of such tablets, pills, semi-solid substances,coated tablets, dragees and hard gelatine capsules, the therapeuticallyusable product may be mixed with pharmacologically inert, inorganic ororganic pharmaceutical carrier substances, for example with lactose,sucrose, glucose, gelatine, malt, silica gel, starch or derivativesthereof, talcum, stearic acid or salts thereof, skimmed milk powder, andthe like. For the preparation of soft capsules, pharmaceutical carriersubstances such as, for example, vegetable oils, petroleum, animal orsynthetic oils, wax, fat and polyols may be used.

For the preparation of liquid solutions and syrups, pharmaceuticalcarrier substances such as, for example, water, alcohols, aqueous salinesolution, aqueous dextrose, polyols, glycerol, vegetable oils, petroleumand animal or synthetic oils may be used.

For suppositories, pharmaceutical carrier substances such as, forexample, vegetable oils, petroleum, animal or synthetic oils, wax, fatand polyols may be used.

For aerosol formulations, compressed gases that are suitable for thispurpose, such as, for example, oxygen, nitrogen and carbon dioxide maybe used. The pharmaceutically acceptable agents may also compriseadditives for preserving and stabilising, emulsifiers, sweeteners,flavourings, salts for altering the osmotic pressure, buffers,encapsulation additives and antioxidants.

Combinations with other therapeutic agents which are also encompassed bythe present invention may comprise one, two or more other antimicrobialand anti-fungal active ingredients.

For the prevention and/or treatment of bacterial infections, the dose ofthe biologically active compound according to the invention may varywithin wide limits and may be adjusted to individual requirements.Generally, a dose of 10 mg to 4000 mg per day is suitable, a preferreddose being from 50 to 3 000 mg per day. In suitable cases, the dose mayalso be below or above the stated values. The daily dose may beadministered as a single dose or in a plurality of doses. A typicalindividual dose contains approximately 50 mg, 100 mg, 250 mg, 500 mg, 1g or 2 g of the active ingredient.

EXAMPLES

Particular embodiments of the invention are described in the followingExamples, which serve to illustrate the invention in more detail:

All reagents and anhydrous solvents are generally used as received fromthe commercial supplier;reactions are routinely performed in well-dried glassware under an argonor nitrogen atmosphere;evaporations are carried out by rotary evaporation in vacuo and work-upprocedures are carried out after removal of residual solids byfiltration;all temperatures are given in ° C.; operations are carried at roomtemperature, that is typically in the range 18-25° C.;column chromatography (by the flash procedure) is used to purifycompounds and is performed using Merck silica gel 60 (70-230 mesh ASTM)unless otherwise stated;in general, the course of reactions is followed by TLC, HPLC, or LC/MSand reaction times are given for illustration only; yields are given forillustration only and are not necessarily the maximum attainable;the structure of the final products of the invention is generallyconfirmed by NMR and mass spectral techniques. Proton NMR spectra arerecorded on a Brucker 400 MHz spectrometer. Chemical shifts (δ) arereported in ppm relative to Me₄Si as internal standard, and J values arein Hertz (Hz). Each peak is denoted as a broad singlet (br), singlet(s), doublet (d), doublet of doublets (dd), triplet of doublets (td) ormultiplet (m). Mass spectra are generated using a q-T of Ultima (WatersAG) mass spectrometer in the positive ESI mode. The system is equippedwith the standard Lockspray interface;each intermediate is purified to the standard required for thesubsequent stage and is characterized in sufficient detail to confirmthat the assigned structure is correct;all analytical and preparative HPLC investigations on non-chiral phasesare performed using RP-C18 based columns;the following abbreviations may be used:Acetone-d6: Deuterated acetoneCDCl₃: Deuterated chloroformDMSO-d6: Deuterated dimethyl sulphoxideELSD: Evaporative light scattering detectionHPLC: High performance liquid chromatographyJ: Coupling constantLC/MS: Liquid chromatography coupled to mass spectroscopyMeOH-d4: Deuterated methanol

Me₄Si: Tetramethylsilane

MS: Mass spectroscopyNMR: Nuclear magnetic resonanceTLC: Thin layer chromatography

The following Examples refer to the compounds of formula I as indicatedin Table 1 (A in Table 1 is O when A1 in formula (I) is—O—(CH₂)_(m)—(CH₂)— or S when A1 is —S—(CH₂)_(m)—(CH₂)— or CO₂ when A1is —(C═O)O—(CH₂)_(m)—(CH₂)—):

TABLE 1 Exemplified compounds Expl./ Comp.

A

A3 R4 m n G 1 7-Methoxy- quinoxaline O

C═O H 1 0

2 6-Methoxy- [1,5]naphthyridine O

C═O H 1 0

3 6-Methoxy- [1,5]naphthyridine O

C═O H 1 0

4 7-Methoxy- quinoxaline O

C═O H 1 0

5 7-Methoxy- quinoxaline O

C═O H 1 0

6 6-Methoxy- [1,5]naphthyridine O

C═O H 1 0

7 7-Fluoro-quinoxaline O

C═O H 1 0

8 7-Methoxy- quinoxaline O

CH₂ H 2 0

9 7-Methoxy- quinoxaline O

CH₂ H 2 1

10 7-Methoxy- quinoxaline O

CH₂ Me 1 0

11 7-Methoxy- quinoxaline O

CH₂ H 2 0

12 8-Methoxy- quinoxaline O

C═O H 1 0

13 7-Nitro-quinoxaline O

C═O H 1 0

14* 7-Methoxy- quinoxaline O

C═O H 1 0

15 7-Methoxy- quinoxaline O

C═O H 1 0

16 6-Methoxy- [1,5]naphthyridine O

C═O H 1 0

17 7-Methoxy-quinoline O

C═O H 1 0

18 7-Methoxy- [1,5]naphthyridine O

C═O H 1 0

19 7-Methoxy- [1,5]naphthyridine O

C═O H 1 0

20 7-Methoxy- quinoxaline O

C═O H 1 0

21 Quinoxaline O

C═O H 1 0

22 7-Methoxy- quinoxaline O

C═O H 1 0

23 7-Methoxy- quinoxaline O

C═O H 2 0

24 7-Methoxy- quinoxaline O

C═O H 1 1

25 7-Methoxy- quinoxaline O

CH₂ Me 1 0

26 7-Methoxy- quinoxaline O

C═O H 1 1

27 7-Methoxy- quinoxaline O

C═O H 2 1

28 6-Methoxy-quinoline CO₂

C═O H 0 0

29 6-Methoxy- [1,5]naphthyridine CO₂

CH₂ H 0 0

30 6-Methoxy- [1,5]naphthyridine CO₂

C═O H 0 0

31 6-Methoxy- [1,5]naphthyridine CO₂

C₂H₄—S H 0 0

32 6-Methoxy-quinoline CO₂

CH₂ Me 0 0

33 6-Methoxy-quinoline CO₂

CH₂ H 0 0

34 6-Methoxy-quinoline CO₂

CH₂ Et 0 0

35 7-Methoxy- quinoxaline S

C═O H 1 0

36 7-Methoxy- quinoxaline S

C═O H 1 0

37 7-Methoxy- quinoxaline S

C═O H 1 0

38 7-Methoxy- quinoxaline S

C₂H₄—S H 1 0

39 7-Methoxy- quinoxaline S

C═O H 1 0

40 7-Methoxy- quinoxaline S

CH₂ H 1 0

41 7-Methoxy- quinoxaline S

CH₂ H 1 0

42 7-Methoxy- quinoxaline S

CH₂ H 1 0

43 7-Methoxy- quinoxaline S

CH₂ Me 1 0

44 7-Methoxy- quinoxaline S

C═O H 1 0

45 7-Methoxy- quinoxaline S

CH₂ H 1 0

46 7-Methoxy- quinoxaline S

CH₂ H 1 0

47 7-Methoxy- quinoxaline S

CH₂ Et 1 0

48 7-Methoxy- quinoxaline S

CH₂ H 1 0

49 7-Methoxy- quinoxaline S

CH₂ H 1 0

50 7-Methoxy- quinoxaline S

C═O H 1 0

51 7-Methoxy- quinoxaline S

C═O H 1 0

52 7-Methoxy- quinoxaline S

C═O Me 1 0

53 6-Methoxy-quinoline S

C═O H 1 0

54 6-Methoxy-quinoline S

C═O H 1 0

55 6-Methoxy-quinoline S

C═O H 1 0

56 6-Methoxy-quinoline S

C═O H 1 0

57 7-Hydroxy- quinoxaline O

C═O H 1 0

58 7-Ethoxy- quinoxaline O

C═O H 1 0

59 Acetic acid- quinoxalin-6-yl ester O

C═O H 1 0

60 Methanesulfonic acid-quinoxalin-6-yl ester O

C═O H 1 0

61 (Quinoxalin-6-yloxy)- acetic acid methyl ester O

C═O H 1 0

62 7-Difluoromethoxy- quinoxaline O

C═O H 1 0

63* 7-Methoxy- quinoxaline O

C═O H 1 0

64* 7-Methoxy- quinoxaline O

C═O H 1 0

65* 7-Methoxy- quinoxaline S

C═O H 1 0

66 7-Methoxy- quinoxaline O

C═O H 1 0

67 7-Methoxy- quinoxaline S

C═O H 1 0

68 7-Methoxy-3-methyl- quinoxaline O

C═O H 1 0

69 7-Methylsulfanyl- quinoxaline O

C═O H 1 0

70 3-Methoxy-quinoline O

C═O H 1 0

71 2-Methoxy-quinoline O

C═O H 1 0

72 7-Cyano-quinoxaline O

C═O H 1 0

73 7-Fluoro-6-methoxy- quinoline O

CH₂ H 1 0

74 7-Methoxy- quinoline-3- carboxy acid O

C═O H 1 0

75* 7-Methoxy- quinoxaline O

CH₂ H 1 0

76 7,8-Dimethoxy- quinoxaline S

C═O H 1 0

77 4-Ethoxy-6-methoxy- [1,5]naphthyridine O

C═O H 1 0

78 7-Methoxy- quinoxaline O

C═O H 1 0

79 7-Methoxy- quinoxaline O

C═O H 1 0

80 7-Methoxy- quinoxaline O

C═O H 1 0

81 7-Methoxy- quinoxaline O

C═O H 1 0

82 7-(2-Methoxy- ethoxy)-quinoxaline O

C═O H 1 0

83 Isoxazole-5- carboxylic acid- quinoxalin-6-yl ester O

C═O H 1 0

84 Methoxy-acetic acid- quinoxalin-6-yl ester O

C═O H 1 0

85 7-[2-(4- Difluoromethoxy- phenyl)-2-oxo- ethoxy]-quinoxaline O

C═O H 1 0

86 (Quinoxalin-6-yloxy)- acetic acid tert-butyl ester O

C═O H 1 0

87 7-(2-Oxo-butoxy)- quinoxaline O

C═O H 1 0

88 7-Isopropoxy- quinoxaline O

C═O H 1 0

89 7-(2-Phenoxy- ethoxy)-quinoxaline O

C═O H 1 0

90 7-(2-[1,3]Dioxan-2- yl-ethoxy)- quinoxaline O

C═O H 1 0

91 7-(3-Hydroxy- propoxy)-quinoxaline O

C═O H 1 0

92 7-(3-Cyano- propoxy)-quinoxaline O

C═O H 1 0

93 7-Propoxy- quinoxaline O

C═O H 1 0

94* 7-Methoxy- quinoxaline O

C═O H 1 0

95* 7-Methoxy- quinoxaline O

C═O H 1 0

96* 7-Methoxy- quinoxaline O

CH₂ H 1 0

97* 7-Methoxy- quinoxaline O

C═O H 1 0

98 7-Methoxy- quinoxaline O

CH₂ H 1 0

99 7-Methoxy- quinoxaline O

C═O H 1 0

100 8-Hydroxy-quinoline CO₂

C═O H 0 0

101 2-Chloro-6-methoxy- quinoline CO₂

C═O H 0 0

102 6-Methoxy- [1,5]naphthyridine S

CH₂ H 1 0

103 6-Methoxy- [1,5]naphthyridine S

C═O H 1 0

104 7-Methoxy- quinoxaline S

C═O H 1 1

105 7-Methoxy- quinoxaline S

CH₂ H 1 0

106* 7-Methoxy- quinoxaline O

C═O H 1 0

107* 7-Methoxy- quinoxaline O

C═O H 1 0

108* 7-Methoxy- quinoxaline O

C═O H 1 0

109* 7-Methoxy- quinoxaline O

C═O H 1 0

110 7-Methoxy- quinoxaline O

CH₂ H 1 0

111 7-Methoxy- quinoxaline O

C═O H 1 0

112 7-Methoxy- quinoxaline O

C═O H 1 0

113 6-Methoxy-quinoline CO₂

CH₂ H 0 0

114 6-Methoxy-quinoline CO₂

CH₂ H 0 0

115 6-Methoxy-quinoline CO₂

CH₂ H 0 0

116 6-Methoxy-quinoline CO₂

—(CH₂)— CH═CH— H 0 0

117 6-Methoxy-quinoline CO₂

CH₂ H 0 0

118 6-Methoxy-quinoline CO₂

CH₂ H 0 0

119 6-Methoxy-quinoline CO₂

CH₂ H 0 0

120 6-Methoxy-quinoline CO₂

—(CH₂)₃— H 0 0

121 6-Methoxy-quinoline CO₂

CH₂ H 0 0

122 7-Methoxy- quinoxaline S

C═O H 1 0

123 7-Methoxy- quinoxaline O

CH₂ H 1 0

*For Example 14 the group A1 has the formula: —O—CH(CF₃)—CH₂—; ForExample 63 the group A1 has the formula: —O—CH(CH₂OCH₃)—CH₂—; ForExample 64 the group A1 has the formula: —O—CH(CH₂OCH₂CH₂OCH₃)—CH₃—; ForExample 65 the group A1 has the formula: —S—CH(CH₂-morpholino)-CH₂—; ForExample 75 the group A1 has the formula: —O—CH(cyclopropyl)-CH₂—; ForExample 94 the group A1 has the formula: —O—CH(CH₃)—CH₂—; For Example 95the group A1 has the formula: —O—CH(CH₂F)—CH₂—;

The numbers of the compounds of formula I used in the leftmost column ofTable 1 is used in the whole application text for identifying therespective compounds, e.g. in Table 2 referring to the results in thetests for biological activity.

Example 1 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amidePreparation of [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acidtert-butyl ester

2-Bromo-ethanol (2.38 mL, 33.5 mmol, 1.0 eq) is added at roomtemperature to a stirred solution of piperidin-4-yl-carbamic acidtert-butyl ester (7.0 g, 33.5 mmol, 1.0 eq) in N,N-dimethylformamide(300 mL), followed by potassium carbonate (4.64 g, 33.5 mmol, 1.0 eq).After 6 hours stirring at room temperature, solvent is evaporated andthe residue is extracted with ethyl acetate (3×40 mL) and water (40 mL).pH of the aqueous layer is neutralized with a 0.1 N hydrochloric acidaqueous solution. The combined organic layers are dried over sodiumsulfate, filtered and concentrated to afford[1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester asan off-white oil (7.96 g, 97% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 6.75 (d, J=7.6 Hz, 1H), 4.40 (br, 1H),3.47 (t, J=6.2 Hz, 2H), 3.32 (br, 1H), 3.17 (br, 1H), 2.80 (m, 2H), 2.36(t, J=6.2 Hz, 2H), 1.97 (m, 2H), 1.68 (m, 2H), 1.37 (m, 10H).

MS m/z (+ESI): 245.3 [M+H]⁺.

Preparation of{1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester

Sodium hydride (55% purity, 62 mg, 1.48 mmol, 1.5 eq) is added at roomtemperature to a stirred solution of 2-chloro-7-methoxy-quinoxaline (200mg, 0.99 mmol, 1.0 eq) in N,N-dimethylformamide (10 mL), followed by[1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (268mg, 0.99 mmol, 1.0 eq). After 4 hours stirring at room temperature,solvent is evaporated, and the residue is extracted with dichloromethane(3×20 mL) and water (20 mL). The combined organic layers are dried oversodium sulfate, filtered and concentrated to give a residue that ispurified by column chromatography (silica gel, eluent: cyclohexane:ethylacetate:methanol, 1:1:0 to 0:9:1, v/v/v) to afford{1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester as an orange solid (210 mg, 52% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.41 (s, 1H), 7.88 (d, J=9.0 Hz, 1H),7.20-7.28 (m, 2H), 6.75 (br, 1H), 4.52 (t, J=5.8 Hz, 2H), 3.92 (s, 3H),3.25 (m, 1H), 2.92 (m, 2H), 2.73 (m, 2H), 2.10 (m, 2H), 1.68 (m, 2H),1.37 (m, 11H).

MS m/z (+ESI): 403.2 [M+H]⁺.

Preparation of1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-ylamine

Trifluoroacetic acid (580 μL, 7.52 mmol, 15.0 eq) is added at 0° C. to astirred solution of{1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester (206 mg, 0.50 mmol, 1.0 eq) in dichloromethane (20mL). After 15 hours stirring at room temperature, the reaction mixtureis extracted with dichloromethane (3×20 mL) and water (20 mL) and the pHis adjusted to 12 by the addition of a 1N sodium hydroxide aqueoussolution. The combined organic layers are dried over sodium sulfate,filtered and concentrated to afford1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-ylamine as anorange oil (155 mg, 99.5% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.41 (s, 1H), 7.88 (d, J=9.0 Hz, 1H),7.20-7.28 (m, 2H), 4.52 (t, J=5.9 Hz, 2H), 3.93 (s, 3H), 2.88 (m, 2H),2.73 (t, J=5.9 Hz, 2H), 2.08 (td, J=2.3, 11.5, 2H), 1.68 (m, 2H), 1.45(br, 1H), 1.22 (m, 2H).

MS m/z (+ESI): 303.3 [M+H]⁺.

Preparation of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide

3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (60 mg, 0.26mmol, 1.0 eq) is added at room temperature to a stirred solution of1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-ylamine (80 mg,0.26 mmol, 1.0 eq) in N,N-dimethylformamide (5 mL), followed by1-hydroxybenzotriazole (38 mg, 0.29 mmol, 1.1 eq),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (57 mg,0.30 mmol, 1.15 eq) and N,N-diisopropylethylamine (100 μL, 0.58 mmol,2.25 eq). After 15 hours stirring at room temperature, solvent isevaporated and the residue is extracted with dichloromethane (3×10 mL)and water (10 mL). The combined organic layers are dried over sodiumsulfate, filtered and concentrated to give a residue that is purified bypreparative HPLC to afford3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide as anoff-white solid (18 mg, 13% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.65 (s, 1H), 8.42 (s, 1H), 8.22 (d,J=7.8 Hz, 1H), 7.89 (d, J=9.0 Hz, 1H), 7.38-7.46 (m, 3H), 7.22-7.28 (m,2H), 4.56 (t, J=5.8 Hz, 2H), 3.92 (s, 3H), 3.75 (m, 1H), 3.50 (s, 2H),3.00 (m, 2H), 2.81 (t, J=5.8 Hz, 2H), 2.18 (m, 2H), 1.79 (m, 2H), 1.55(m, 2H).

MS m/z (+ESI): 494.4 [M+H]⁺.

Example 2 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{trans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexyl}-amidePreparation of 2-[(6-methoxy-pyridin-3-ylamino)-methylene]-malonic aciddiethyl ester

A solution of 3-amino-6-methoxy-pyridine (200.0 g, 1611.05 mmol, 1.0 eq)and 2-ethoxymethylene-malonic acid diethyl ester (348.4 g, 1611.05 mmol,1.0 eq) in toluene (650 mL) is heated to reflux and the ethanol formedis removed by azeotropic distillation. After 2.5 hours at 115° C., thereaction mixture is cooled to room temperature, the solvent is removedand the resulting solid is washed with 500 mL of hexane then dried undervacuum to afford 2-[(6-methoxy-pyridin-3-ylamino)-methylene]malonic aciddiethyl ester as a red solid (434.0 g, 90% yield).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 10.92 (d, J=13.2 Hz, 1H), 8.36 (d, J=13.2Hz, 1H), 8.02 (d, J=2.8 Hz, 1H), 7.42 (dd, J=2.8, 8.8 Hz, 1H), 6.77 (d,J=8.8 Hz, 1H), 4.33-4.20 (m, 4H), 3.93 (s, 3H), 1.40-1.29 (m, 6H).

MS m/z (+ESI): 295.1 [M+H]⁺.

Preparation of6-methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethylester

A solution of 2-[(6-methoxy-pyridin-3-ylamino)-methylene]malonic aciddiethyl ester (260.0 g, 1.365 mol, 1.0 eq) in diphenyl ether (500 mL) isheated to reflux. While the ethanol formed is removed by azeotropicdistillation the reflux temperature reached 245° C. The reaction mixtureis kept at 245° C. for 3 hours, then it is cooled to 28° C., a brownsolid precipitated and is collected by filtration and washed with hexane(500 mL). The solid is dried under vacuum to afford6-methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethylester as a brown powder (74.2 g, 32% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 12.28 (s, 1H), 8.47 (s, 1H), 7.98 (d,J=9.2 Hz, 1H), 7.18 (d, 1H, J=9.2 Hz), 4.20 (d, J=7.2 Hz, 2H). 3.93 (s,3H), 1.27 (t, J=7.2 Hz, 3H).

MS m/z (+ESI): 249.1 [M+H]⁺.

Preparation of 4-chloro-6-methoxy-[1,5]naphthyridine-3-carboxylic acidethyl ester

A solution of6-methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethylester (110.0 g, 407.67 mmol, 1.0 eq) in phosphorus oxychloride (650 mL)is refluxed for 4 hours. Then the reaction mixture is cooled to roomtemperature and the solvent is evaporated. The residue is poured intoice water and the resulting mixture is basified with 25% ammoniumhydroxide to pH=8˜9 and extracted with ethyl acetate (3×500 mL). Thecombined organic layers are dried over sodium sulfate, filtered andevaporated to give a brown solid as crude product, which is thenpurified by column chromatography (silica gel, eluent: ethylacetate:petroleum ether, 1:4, v/v) to afford4-chloro-6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester as alight yellow solid (78 g, 62% yield).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 9.05 (s, 1H), 8.27 (d, J=9.2 Hz, 1H),7.25 (d, J=9.2 Hz, 1H), 4.52 (q, J=6.8 Hz, 2H), 4.17 (s, 3H), 1.47 (t,J=6.8 Hz, 3H).

MS m/z (+ESI): 267.1 [M+H]⁺.

Preparation of 6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethylester

A mixture of 4-chloro-6-methoxy-[1,5]naphthyridine-3-carboxylic acidethyl ester (75 g, 241.86 mmol, 1.0 eq), triethylamine (75 mL, 538.08mmol, 2.22 eq), and 10% palladium on activated carbon (8.2 g) in ethanol(1350 mL) is stirred under hydrogen flow at room temperature for 6hours. The catalyst is then removed by filtration and the solution isevaporated to dryness to give a yellow solid as crude product, which ispurified by column chromatography (silica gel, eluent: petroleumether:ethyl acetate, 5:1, v/v) to afford6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester as a lightyellow powder (46.2 g, 77% yield).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 9.32 (d, J=2.0 Hz, 1H), 8.77 (d, J=2.0Hz, 1H), 8.25 (d, J=10.0 Hz, 1H), 7.22 (d, J=10.0 Hz, 1H), 4.47 (q,J=6.8 Hz, 2H), 4.10 (s, 3H), 1.46 (t, J=6.8 Hz, 3H).

MS m/z (+ESI): 233.1 [M+H]⁺.

Preparation of 6-methoxy-[1,5]naphthyridine-3-carboxylic acid

A mixture of 6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester(32.0 g, 74.45 mmol, 1.0 eq) and sodium hydroxide (10.12 g, 137.51 mmol,1.85 eq) in ethanol (110 mL) is refluxed for 3 hours. The solvent isevaporated and the residue is dissolved in water, washed with ethylacetate, then acidified with 3N hydrochloric acid aqueous solution topH=3-4. The precipitate is collected by filtration, dried under 50° C.overnight to afford 6-methoxy-[1,5]naphthyridine-3-carboxylic acid as awhite solid (24.5 g, 82% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 13.60 (br, 1H), 9.19 (t, J=2.0 Hz, 1H),8.55 (d, J=2.0 Hz, 1H), 8.33 (d, J=8.8 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H),4.03 (s, 3H).

MS m/z (+ESI): 205.2 [M+H]⁺.

Preparation of (6-methoxy-[1,5]naphthyridine-3-yl)-carbamic acidtert-butyl ester

A mixture of 6-methoxy-[1,5]naphthyridine-3-carboxylic acid (24.5 g, 120mmol, 1.0 eq), triethylamine (50.2 mL, 360 mmol, 3.0 eq) andtert-butanol (292 mL, 3.54 mol, 32 eq) in dimethylformamide (338 mL) isadded dropwise to diphenyl phosphoryl azide (49.5 g, 180 mmol. 1.5 eq)to form a yellow clear solution. The mixture is stirred at 70° C. for 40minutes then warmed to 100° C. for 3 hours. The mixture is cooled toroom temperature and concentrated to dryness. The residue is purified bycolumn chromatography (silica gel, eluent: dichloromethane:petroleumether:ethyl acetate, 25:25:2, v/v/v) to afford(6-methoxy-[1,5]naphthyridine-3-yl)-carbamic acid tert-butyl ester as ayellow solid (23.15 g, 69% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 9.96 (s 1H), 8.77 (d, J=2.4 Hz, 1H),8.29 (d, J=2.4 Hz, 1H), 8.13 (d, J=9.6 Hz, 1H), 7.05 (d, J=9.6 Hz, 1H),3.97 (s, 3H), 1.50 (s, 9H).

MS m/z (+ESI): 276.3 [M+H]⁺.

Preparation of 3-amino-6-methoxy-[1,5]naphthyridine

Trifluoroacetic acid (101 mL, 1.32 mol, 20.85 eq) is added to a stirredsolution of (6-methoxy-[1,5]naphthyridine-3-yl)-carbamic acid tert-butylester (18.2 g, 66.11 mmol, 1.0 eq) in dichloromethane (500 mL). After 19hours stirring at room temperature, the solution is evaporated todryness, 6N sodium hydroxide aqueous solution is added to adjust pH to9˜10 and a lot of solid precipitated. The mixture is extracted withdichloromethane (200 mL) and the residue is extracted with ethyl acetate(3×250 mL). Evaporation of the dichloromethane phase gives 2.44 g ofproduct with 83% purity, which is then purified by column chromatography(silica gel, eluent: dichloromethane:petroleum ether:ethyl acetate,25:25:2, v/v/v) to afford 6-methoxy-[1,5]naphthyridin-3-ylamino as alight yellow solid (1.95 g with 98% purity). Evaporation of the ethylacetate phase yields additional 9.88 g of light yellow product with 99%purity. Total: 11.83 g (98% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.25 (d, J=2.0 Hz, 1H), 7.99 (d, J=8.8Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 5.90 (s, 2H),3.91 (s, 3H).

MS m/z (+ESI): 176.1 [M+H]⁺.

Preparation of 6-methoxy-[1,5]naphthyridin-3-ol

6-methoxy-[1,5]naphthyridin-3-ylamino (13.6 g, 77.63 mmol, 1.0 eq) isadded to a solution of sulfuric acid (20.7 mL, 388 mmol, 5.0 eq) inwater (177 mL) at 0-4° C. Then a solution of sodium nitrite (5.89 g,85.39 mmol, 1.1 eq) in water (136 mL) is added to this solution. Themixture is stirred at −5° C.-0° C. for 2 hours, then it is allowed tocome at room temperature and stir for 2 hours. After being adjusted topH=7, the mixture is extracted with ethyl acetate (3×250 mL). Theorganic layers are combined, dried over sodium sulfate and concentratedto yield the crude product, which is purified by column chromatography(silica gel, eluent: petroleum ether:ethyl acetate, 8:1 to 1:1, v/v) toafford 6-methoxy-[1,5]naphthyridin-3-ol as a yellow solid (9.7 g, 65%yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.58 (br, 1H), 8.42 (d, J=2.8 Hz, 1H),8.11 (d, J=8.8 Hz, 1H), 7.33 (d, J=2.8 Hz, 1H), 6.97 (d, J=8.8 Hz, 1H),3.95 (s, 3H).

MS m/z (+ESI): 177.1 [M+H]⁺.

Preparation of [trans-4-(2-hydroxy-ethyl)-cyclohexyl]-carbamic acidtert-butyl ester

A solution of borane dimethyl sulphide complex in tetrahydrofuran (11.7mL, 23.32 mmol, 3.0 eq) is added dropwise within 10 minutes at −5° C. toa stirred solution of (4-tert-butoxycarbonylamino-cyclohexyl)-aceticacid (2.0 g, 7.77 mmol, 1.0 eq) in tetrahydrofuran (50 mL). The reactionmixture is stirred at −5° C. for 20 minutes then at room temperature for3 hours. Methanol (10 mL) is cautiously added to the reaction mixturethat is then evaporated and repeatedly treated with methanol andconcentrated to dryness to afford[trans-4-(2-hydroxy-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester asa white solid (1.89 g, 99.5% yield).

¹H-NMR (400 MHz, DMSO-d6), δ ppm: 6.62 (d, J=8.4 Hz, 1H), 4.26 (t, J=5.2Hz, 1H), 3.35-3.41 (m, 2H), 3.12-3.10 (m, 1H), 1.64-1.73 (m, 4H), 1.35(s, 9H), 1.20-1.30 (m, 3H), 1.04-1.13 (m, 2H), 0.83-0.91 (m, 2H).

Preparation of{trans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexyl}-carbamicacid tert-butyl ester

Diethyl azodicarboxylate (3.96 g, 22.72 mmol, 3.0 eq) is added at roomtemperature to a stirred solution of[trans-4-(2-hydroxy-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester(1.84 g, 7.57 mmol, 1.0 eq), 6-methoxy-[1,5]naphthyridin-3-ol (1.80 g,10.22 mmol, 1.35 eq) and triphenylphosphine (5.96 g, 22.72 mmol, 3.0 eq)in tetrahydrofuran (70 mL). After 14 hours stirring at 30° C.,tetrahydrofuran is evaporated and the resulting crude product ispurified by column chromatography (silica gel, eluent: petroleumether:ethyl acetate, 6:1, v/v) to afford{trans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexyl}-carbamicacid tert-butyl ester as an off-white solid (1.65 g, 53.5% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.49 (d, J=2.0 Hz, 1H), 8.16 (d, J=8.8Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 6.67 (d, J=8.0Hz, 1H), 4.18 (t, J=6.4 Hz, 2H), 3.98 (s, 3H), 3.26 (s, 1H), 1.76-1.79(m, 4H), 1.65-1.70 (m, 2H), 1.35 (s, 10H), 0.98-1.14 (m, 4H).

MS m/z (+ESI): 402.2 [M+H]⁺.

Preparation oftrans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexylamine

Trifluoroacetic acid (6.33 mL, 82.2 mmol, 20 eq) is added at roomtemperature to a stirred solution of{trans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexyl}-carbamicacid tort-butyl ester (1.65 g, 4.11 mmol, 1.0 eq) in dichloromethane(100 mL). After 2 hours stirring at room temperature, the reactionmixture is partitioned between saturated sodium hydrogen carbonateaqueous solution and dichloromethane and the pH value is about 10. Thecombined organic layers are dried over sodium sulfate and concentratedto affordtrans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexylamineas a yellow solid (1.24 g, 95% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.49 (d, J=2.4 Hz, 1H), 8.16 (d, J=8.8Hz, 1H), 7.57 (d, J=2.4 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 4.18 (t, J=6.4Hz, 2H), 3.98 (s, 3H), 2.48 (s, 1H), 1.69-1.75 (m, 4H), 1.64-1.67 (m,2H), 1.41 (s, 1H), 0.95-1.00 (m, 4H).

MS m/z (+ESI): 302.3 [M+H]⁺.

Preparation of (3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid{trans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexyl})-amide

3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (59 mg, 0.25mmol, 1.0 eq) is added at room temperature to a stirred solution oftrans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexylamine(80 mg, 0.25 mmol, 1.0 eq) in N,N-dimethylformamide (5 mL), followed by1-hydroxybenzotriazole (37 mg, 0.28 mmol, 1.1 eq),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (56 mg,0.29 mmol, 1.15 eq) and N,N-diisopropylethylamine (97 μL, 0.57 mmol,2.25 eq). After 15 hours stirring at room temperature, solvent isevaporated and the residue is extracted with dichloromethane (3×10 mL)and water (10 mL). The combined organic layers are dried over sodiumsulfate, filtered and concentrated to give a crude product that ispurified by preparative HPLC to afford(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{trans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexyl})-amideas a white lyophilizated powder (36 mg, 27% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.64 (s, 1H), 8.53 (d, J=2.8 Hz, 1H),8.19 (dd, J=0.7, 9.0 Hz, 2H), 7.62 (dd, J=0.5, 2.5 Hz, 1H), 7.37-7.46(m, 3H), 7.07 (d, J=9.0 Hz, 1H), 4.24 (t, J=6.6 Hz, 2H), 4.00 (s, 3H),3.70-3.80 (m, 1H), 3.50 (s, 2H), 1.80-1.90 (m, 4H), 1.70-1.80 (m, 2H),1.45-1.55 (m, 1H), 1.30-1.40 (m, 2H), 1.05-1.18 (m, 2H).

MS m/z (+ESI): 493.4 [M+H]⁺.

Example 3 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxylicacid{trans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexyl}-amide

The title compound is prepared as a white lyophilizated powder (19 mg,15% yield) following Scheme 1 and in analogy to Example 2 using3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxylic acid (49 mg,0.25 mmol 1.0 eq) andtrans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexylamine(80 mg, 0.25 mmol, 1.0 eq) as starting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 11.35 (br, 1H), 8.53 (d, J=2.8 Hz, 1H),8.19 (dd, J=0.7, 9.0 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.61 (m, 2H), 7.46(d, J=8.2 Hz, 1H), 7.07 (d, J=9.0 Hz, 1H), 4.73 (s, 2H), 4.24 (t, J=6.6Hz, 2H), 4.00 (s, 3H), 3.68-3.78 (m, 1H), 1.85-1.95 (m, 4H), 1.70-1.80(m, 2H), 1.48-1.60 (m, 1H), 1.22-1.38 (m, 2H), 1.10-1.22 (m, 2H).

MS m/z (+ESI): 478.4 [M+H]⁺.

Example 4 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{trans-4-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-cyclohexyl}-amide

The title compound is prepared as a white amorphous lyophilizated solidfollowing Scheme 1 and in analogy to Example 2 using2-hydroxy-7-methoxy-quinoxaline,[trans-4-(2-hydroxy-ethyl)-cyclohexyl]-carbamic acid tert-butyl esterand 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid asstarting materials.

MS m/z (+ESI): 493.4 [M+H]⁺, 515.4 [M+Na]⁺.

Example 5 5-thiophen-2-yl-isoxazole-3-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as a yellow solid (39 mg, 30% yield)following Scheme 1 and in analogy to Example 1 using5-thiophen-2-yl-isoxazole-3-carboxylic acid (51 mg, 0.26 mmol 1.0 eq)and 1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-ylamine (80mg, 0.26 mmol, 1.0 eq) as starting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.70 (d, J=7.8 Hz, 1H), 8.42 (s, 1H),7.75-7.90 (m, 3H), 7.20-7.35 (m, 3H), 7.17 (s, 1H), 4.55 (t, J=5.7 Hz,2H), 3.93 (s, 3H), 3.02 (m, 2H), 2.80 (t, J=5.7 Hz, 2H), 2.48 (m, 1H),2.15 (m, 2H), 1.78 (m, 2H), 1.60 (m, 2H).

MS m/z (+ESI): 480.3 [M+H]⁺.

Example 6 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid{trans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexyl}-amide

The title compound is prepared as a white amorphous lyophilizated solid(19 mg, 15% yield) following Scheme 1 and in analogy to Example 2 using3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (50 mg, 0.25mmol 1.0 eq) andtrans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexylamine(80 mg, 0.25 mmol, 1.0 eq) as starting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.80 (s, 1H), 8.53 (d, J=2.8 Hz, 1H),8.19 (dd, J=0.7, 9.0 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.61 (dd, J=0.5,2.4 Hz, 1H), 7.40-7.46 (m, 2H), 7.07 (d, J=9.0 Hz, 1H), 6.97 (d, J=8.3Hz, 1H), 4.63 (s, 2H), 4.24 (t, J=6.6 Hz, 2H), 4.00 (s, 3H), 3.68-3.80(m, 1H), 1.80-1.90 (m, 4H), 1.70-1.80 (m, 2H), 1.45-1.55 (m, 1H),1.25-1.45 (m, 2H), 1.05-1.20 (m, 2H).

MS m/z (+ESI): 477.4 [M+H]⁺.

Example 7 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{trans-4-[2-(7-fluoro-quinoxalin-2-yloxy)-ethyl]-cyclohexyl}-amidePreparation of (4-fluoro-2-nitro-phenylamino)-acetic acid

Bromoacetic acid (5.34 g, 32.0 mmol, 0.5 eq) is added dropwise to4-fluoro-2-nitro-phenylamine (10.0 g, 64.1 mmol, 1.0 eq) at 120° C.After the addition, the reaction mixture is stirred for 2 hours at 120°C. then xylene (10 mL) is added. The resulting reaction mixture isheated at 130° C. for 1 hour, then it is made alkaline with 25% ammoniaaqueous solution. Xylene is removed under reduced pressure and theresidue is diluted with water (100 mL). The mixture is filtered at 60°C. and the insoluble residue is extracted twice with 10% ammonia aqueoussolution at 60° C. The aqueous layer is acidified with hydrochloric acidto pH 5, the precipitated product is filtered, washed with water andethanol, dried under vacuum to afford(4-fluoro-2-nitro-phenylamino)-acetic acid as a red solid (2.98 g, 34%yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.48 (t, J=4.0 Hz, 1H), 7.84 (dd,J=2.8, 9.6 Hz, 1H), 7.50 (td, J=2.8, 9.6 Hz, 1H), 6.93 (dd, J=4.4, 9.6Hz, 1H), 3.87 (d, J=4.0 Hz, 2H).

MS m/z (+ESI): 214.9 [M+H]⁺.

Preparation of 7-fluoro-3,4-dihydro-1H-quinoxalin-2-one

Iron powder (6.52 g, 116.8 mmol, 5.0 eq) is added at room temperature toa stirred solution of (4-fluoro-2-nitro-phenylamino)-acetic acid (6.85g, 23.4 mmol, 1.0 eq) in glacial acetic acid (40 mL). The resultingsuspension is heated at 90° C. for 3 hours, then cooled to roomtemperature, diluted with ethyl acetate (40 mL), and filtered throughsilica gel. The filtrate is concentrated to give a crude that ispurified by column chromatography (silica gel, eluent: ethylacetate:petroleum ether, 1:3, v/v) to afford7-fluoro-3,4-dihydro-1H-quinoxalin-2-one as a brown solid (4.01 g, 72%yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.28 (s, 1H), 6.63-6.51 (m, 3H), 5.87(s, 1H), 3.66 (d, J=2.0 Hz, 2H).

MS m/z (+ESI): 167.1 [M+H]⁺.

Preparation of 7-fluoro-quinoxalin-2-ol

A mixture of 7-fluoro-3,4-dihydro-1H-quinoxalin-2-one (4.00 g, 24.1mmol, 1.0 eq), sodium hydroxide (1.93 g, 48.2 mmol, 2.0 eq) and of 3%hydrogen peroxide solution (50 mL) is refluxed for 2 hours, then it isacidified by slow addition of acetic acid. The resulting mixture iscooled to room temperature, the precipitated solid is collected byfiltration, washed with ice-water, and dried under vacuum to give acrude that is purified by column chromatography (silica gel, eluent:dichloromethane:methanol, 50:1, v/v) to afford 7-fluoro-quinoxalin-2-olas a yellow solid (2.60 g, 69% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 12.48 (s, 1H), 8.10 (s, 1H), 7.80 (dd,J=2.8, 8.8 Hz, 1H), 7.13 (td, J=2.8, 8.8 Hz, 1H), 7.00 (dd, J=2.8, 9.6Hz, 1H).

MS m/z (+ESI): 165.1 [M+H]⁺.

Preparation of 2-chloro-7-fluoro-quinoxaline

A mixture of 7-fluoro-quinoxalin-2-ol (2.60 g, 15.84 mmol, 1.0 eq) andphosphorus oxychloride (50 mL, 536.4 mmol, 34.0 eq) is refluxed for 1hour, then concentrated, diluted with water (60 mL), basified to pH 7 byadding saturated sodium hydrogen carbonate aqueous solution, andextracted with ethyl acetate (3×100 mL). The combined organic layers aredried over sodium sulfate, filtered and concentrated to give a crudethat is purified by column chromatography (silica gel, eluent: ethylacetate:petroleum ether, 1:20, v/v) to afford2-chloro-7-fluoro-quinoxaline as a white solid (2.50 g, 84% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.98 (s, 1H), 8.22 (dd, J=2.0, 8.8 Hz,1H), 7.81-7.89 (m, 2H).

MS m/z (+EI): 183.0 [M+H]⁺.

Preparation of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{trans-4-[2-(7-fluoro-quinoxalin-2-yloxy)-ethyl]-cyclohexyl}-amide

The title compound is prepared as a white amorphous lyophilizated solidfollowing Scheme 1 and in analogy to Example 1 using2-chloro-7-fluoro-quinoxaline,[trans-4-(2-hydroxy-ethyl)-cyclohexyl]-carbamic acid tert-butyl esterand 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid asstarting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.65 (s, 1H), 8.58 (s, 1H), 8.20 (d,J=8.0 Hz, 1H), 8.09 (dd, J=6.0, 9.0 Hz, 1H), 7.52-7.64 (m, 2H),7.37-7.47 (m, 3H), 4.51 (t, J=6.8 Hz, 2H), 3.71 (m, 1H), 3.50 (s, 2H),2.85 (m, 4H), 2.76 (m, 2H), 1.50 (m, 1H), 1.35 (m, 2H), 1.12 (m, 2H).

MS m/z (+ESI): 481.2 [M+H]⁺.

Example 8 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[3-(7-methoxy-quinoxalin-2-yloxy)-propyl]-azetidin-3-yl}-amide

The title compound is prepared as an off-white lyophilizated powderfollowing Scheme 1 and in analogy to Example 1 using2-chloro-7-methoxy-quinoxaline, 3-bromo-propan-1-ol,azetidin-3-yl-carbamic acid tert-butyl ester and3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as startingmaterials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.70 (s, 1H), 8.79 (d, J=6.9 Hz, 1H),8.39 (s, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.40-7.50 (m, 3H), 7.20-7.28 (m,2H), 4.37-4.42 (m, 3H), 3.92 (s, 3H), 3.65 (t, J=7.3 Hz, 2H), 3.51 (s,2H), 3.06 (t, J=7.3 Hz, 2H), 2.65 (m, 2H), 1.85 (m, 2H).

MS m/z (+ESI): 480.2 [M+H]⁺.

Example 96-[({1-[3-(7-methoxy-quinoxalin-2-yloxy)-propyl]-piperidin-4-ylmethyl}-amino)-methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-onePreparation ofC-{1-[3-(7-methoxy-quinoxalin-2-yloxy)-propyl]-piperidin-4-yl}-methylamine

The title compound is prepared as a brown viscous oil following Scheme 1and in analogy to Example 1 using 2-chloro-7-methoxy-quinoxaline,3-bromo-propan-1-ol and piperidin-4-ylmethyl-carbamic acid tert-butylester as starting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.40 (s, 1H), 7.88 (d, J=8.9 Hz, 1H),7.21-7.27 (m, 2H), 4.44 (t, J=6.6 Hz, 2H), 3.92 (s, 3H), 2.89 (m, 2H),2.37-2.48 (m, 4H), 1.97 (m, 2H), 1.82 (m, 2H), 1.65 (m, 2H), 1.00-1.22(m, 3H).

MS m/z (+ESI): 331.3 [M+H]⁺.

Preparation of6-[({1-[3-(7-methoxy-quinoxalin-2-yloxy)-propyl]-piperidin-4-ylmethyl}-amino)-methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one

3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (22 mg,0.12 mmol 1.0 eq) is added at room temperature to a stirred solution ofC-{1-[3-(7-methoxy-quinoxalin-2-yloxy)-propyl]-piperidin-4-yl}-methylamine(40 mg, 0.12 mmol, 1.0 eq) in 1,2-dichloroethane (2 mL) and methanol(0.5 mL), followed by acetic acid (9 μL, 0.15 mmol, 1.3 eq) and sodiumcyanoborohydride (11 mg, 0.15 mmol, 1.3 eq). After 15 hours stirring atroom temperature, the reaction mixture is extracted with dichloromethane(3×5 mL) and a saturated sodium hydrogen carbonate aqueous solution (5mL). The combined organic layers are dried over sodium sulfate, filteredand concentrated to give a residue that is purified by preparative HPLCto afford6-[({1-[3-(7-methoxy-quinoxalin-2-yloxy)-propyl]-piperidin-4-ylmethyl}-amino)-methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-oneas a white viscous oil (18 mg, 29% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 11.20 (br, 1H), 8.39 (s, 1H), 8.20 (s,1H), 7.88 (d, J=9.0 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.25 (m, 2H), 7.01(d, J=8.1 Hz, 1H), 4.63 (s, 2H), 4.45 (t, J=6.5 Hz, 2H), 3.92 (s, 3H),3.70 (s, 2H), 2.94 (d, J=11.2 Hz, 2H), 2.43 (m, 4H), 1.88-2.04 (m, 4H),1.69 (m, 2H), 1.44 (m, 1H), 1.15 (m, 2H).

MS m/z (+ESI): 493.3 [M+H]⁺.

Example 10(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-{1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-methyl-aminePreparation of4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-amino]-piperidine-1-carboxylicacid tert-butyl ester

2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (153 mg, 0.93 mmol, 1.0 eq)is added at room temperature to a stirred solution of4-methylamino-piperidine-1-carboxylic acid tert-butyl ester (200 mg,0.93 mmol, 1.0 eq) in 1,2-dichloroethane (8 mL) and methanol (2 mL),followed by acetic acid (61 μL, 1.07 mmol, 1.15 eq) and sodiumcyanoborohydride (76 mg, 1.21 mmol, 1.3 eq). After 15 hours stirring atroom temperature, the reaction mixture is extracted with dichloromethane(3×20 mL) and a saturated sodium hydrogen carbonate aqueous solution (20mL). The combined organic layers are dried over sodium sulfate, filteredand concentrated to give a residue that is purified by columnchromatography (silica gel, eluent: cyclohexane:ethyl acetate, 3:1 to1:3, v/v) to afford4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-amino]-piperidine-1-carboxylicacid tert-butyl ester as an off-white oil (195 mg, 55% yield).

MS m/z (+ESI): 363.2 [M+H]⁺.

Preparation of(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-piperidin-4-yl-amine

Trifluoroacetic acid (591 μL, 7.67 mmol, 15.0 eq) is added at 0° C. to astirred solution of4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-amino]-piperidine-1-carboxylicacid tert-butyl ester (195 mg, 0.51 mmol, 1.0 eq) in dichloromethane (10mL). After 3 hours stirring at room temperature, the reaction mixture isextracted with dichloromethane (3×10 mL) and water (10 mL) and the pH isadjusted to 12 by the addition of a 1N sodium hydroxide aqueoussolution. The combined organic layers are dried over sodium sulfate,filtered and concentrated to afford(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-piperidin-4-yl-amine asa light yellow solid (148 mg, 99% yield).

MS m/z (+ESI): 263.2 [M+H]⁺.

Preparation of2-{4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-amino]-piperidin-4-yl}-ethanol

2-Bromo-ethanol (36 μL, 0.51 mmol, 1.0 eq) is added at room temperatureto a stirred solution of(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-piperidin-4-yl-amine(148 mg, 0.51 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed bypotassium carbonate (70 mg, 0.51 mmol, 1.0 eq). After 15 hours stirringat room temperature, solvent is evaporated and the residue is extractedwith ethyl acetate (3×8 mL) and water (8 mL). pH of the aqueous layer isneutralized with a 0.1 N hydrochloric acid aqueous solution. Thecombined organic layers are dried over sodium sulfate, filtered andconcentrated to afford2-{4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-amino]-piperidin-4-yl}-ethanolas a yellow semisolid (160 mg, 93% yield).

MS m/z (+ESI): 307.3 [M+H]⁺.

Preparation of(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-{1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-methyl-amine

Sodium hydride (55% purity, 20 mg, 0.47 mmol, 1.0 eq) is added at roomtemperature to a stirred solution of 2-chloro-7-methoxy-quinoxaline (95mg, 0.47 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed by2-{4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-amino]-piperidin-4-yl}-ethanol(160 mg, 0.47 mmol, 1.0 eq). After 4 hours stirring at room temperature,solvent is evaporated, and the residue is extracted with dichloromethane(3×10 mL) and water (10 mL). The combined organic layers are dried oversodium sulfate, filtered and concentrated to give a residue that ispurified by preparative HPLC to afford(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-{1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-methyl-amineas a light yellow oil (11 mg, 5% yield).

MS m/z (+ESI): 465.4 [M+H]⁺.

Example 116-({1-[3-(7-methoxy-quinoxalin-2-yloxy)-propyl]-piperidin-3-ylamino}-methyl)-4H-benzo[1,4]thiazin-3-one

The title compound is prepared as a yellow amorphous lyophilizated solidfollowing Scheme 1 and in analogy to Examples 1 and 9 using2-chloro-7-methoxy-quinoxaline, 3-bromo-propan-1-ol,piperidin-3-yl-carbamic acid tert-butyl ester and3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde as startingmaterials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.52 (s, 1H), 8.39 (s, 1H), 7.88 (d,J=9.0 Hz, 1H), 7.25 (m, 3H), 6.95 (m, 2H), 4.46 (m, 2H), 3.92 (s, 3H),3.67 (s, 2H), 3.57 (s, 2H), 2.70-2.90 (m, 2H), 2.43 (m, 3H), 1.94 (m,3H), 1.79 (m, 2H), 1.60 (m, 1H), 1.39 (m, 1H), 1.07 (m, 1H).

MS m/z (+ESI): 494.3 [M+H]⁺.

Example 12 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(8-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amidePreparation of{1-[2-(8-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester

Sodium hydride (98% purity, 148 mg, 6.10 mmol, 1.5 eq) is added at roomtemperature to a stirred solution of 2-chloro-8-methoxy-quinoxaline (800mg, 4.07 mmol, 1.0 eq) in N,N-dimethylformamide (80 mL), followed by[1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester(1.17 g, 4.07 mmol, 1.0 eq). After 15 hours stirring at room temperatureand 4 hours at 80° C., solvent is evaporated, and the residue isextracted with dichloromethane (3×30 mL) and water (30 mL). The combinedorganic layers are dried over sodium sulfate, filtered and concentratedto give a residue that is purified by column chromatography (silica gel,eluent: cyclohexane:ethyl acetate:methanol, 1:3:0 to 0:9:1, v/v/v) toafford{1-[2-(8-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester as an orange solid (825 mg, 48% yield).

MS m/z (+ESI): 403.3 [M+H]⁺.

Preparation of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(8-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as an off-white lyophilizated powderfollowing Scheme 1 and in analogy to Example 1 using{1-[2-(8-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester and3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as startingmaterials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.65 (s, 1H), 8.60 (s, 1H), 8.21 (d,J=7.7 Hz, 1H), 7.55-7.60 (m, 2H), 7.37-7.44 (m, 3H), 7.26 (dd, J=1.8,6.7 Hz, 1H), 4.57 (t, J=5.6 Hz, 2H), 3.97 (s, 3H), 3.75 (m, 1H), 3.50(s, 2H), 3.03 (m, 2H), 2.80 (t, J=5.6 Hz, 2H), 2.18 (m, 2H), 1.78 (m,2H), 1.55 (m, 2H).

MS m/z (+ESI): 494.4 [M+H]⁺.

Example 13 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-nitro-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as a yellow lyophilizated powderfollowing Scheme 1 and in analogy to Examples 1 and 12 using2-chloro-7-nitro-quinoxaline,[1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as startingmaterials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.65 (s, 1H), 8.83 (s, 1H), 8.61 (d,J=2.5 Hz, 1H), 8.38 (m, 1H), 8.19-8.28 (m, 2H), 7.38-7.46 (m, 3H), 4.64(t, J=5.8 Hz, 2H), 3.78 (m, 1H), 3.58 (s, 2H), 3.02 (m, 2H), 2.82 (t,J=5.8 Hz, 2H), 2.18 (m, 2H), 1.77 (m, 2H), 1.55 (m, 2H).

MS m/z (+ESI): 509.2 [M+H]⁺.

Example 14 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[3,3,3-trifluoro-2-(7-methoxy-quinoxalin-2-yloxy)-propyl]-piperidin-4-yl}-amide

The title compound is prepared as an off-white lyophilizated powderfollowing Scheme 1 and in analogy to Example 1 using2-chloro-7-methoxy-quinoxaline, 3-bromo-1,1,1-trifluoro-2-propanol,piperidin-4-yl-carbamic acid tert-butyl ester and3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as startingmaterials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.61 (s, 1H), 8.58 (s, 1H), 8.10 (d,J=7.5 Hz, 1H), 7.97 (d, J=9.0 Hz, 1H), 7.25-7.40 (m, 5H), 6.30 (m, 1H),3.93 (s, 3H), 3.68 (m, 1H), 3.48 (s, 2H), 3.15 (m, 1H), 2.82-3.00 (m,3H), 2.00-2.35 (m, 2H), 1.65 (m, 2H), 1.15-1.35 (m, 2H).

MS m/z (+ESI): 562.3 [M+H]⁺.

Example 15 7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid {1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as white lyophilizated powder (11 mg, 16%yield) following Scheme 1 and in analogy to Example 1 using7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (31mg, 0.13 mmol, 1.0 eq) and1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-ylamine (40 mg,0.13 mmol, 1.0 eq) as starting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.70 (s, 1H), 8.42 (s, 1H), 8.35 (d,J=7.6 Hz, 1H), 7.89 (d, J=8.9 Hz, 1H), 7.49 (s, 1H), 7.26 (d, J=9.2 Hz,1H), 7.22 (s, 1H), 6.95 (s, 1H), 4.55 (m, 2H), 3.93 (s, 3H), 3.72 (m,1H), 3.51 (s, 2H), 2.96 (m, 2H), 2.79 (m, 2H), 2.18 (m, 2H), 1.79 (m,2H), 1.50 (m, 2H).

MS m/z (+ESI): 528.2 [M+H]⁺.

Example 16 7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid{1-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-amidePreparation of{1-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester

[1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (50mg, 0.19 mmol, 1.0 eq) is added at room temperature to a stirredsolution of 6-methoxy-[1,5]naphthyridin-3-ol (37 mg, 0.19 mmol, 1.0 eq)in tetrahydrofuran (5 mL), followed by triphenylphosphine polymer-bound(3 mmol/g, 193 mg, 0.58 mmol, 3.0 eq) and diisopropyl azodicarboxylate(115 μL, 0.58 mmol, 3.0 eq). After 3 hours stirring at room temperature,the polymer-bound is filtered off and washed successively withtetrahydrofuran (5 mL), dichloromethane (5 mL) and methanol (5 mL). Theresulting solution is concentrated and the residue is extracted withethyl acetate (3×10 mL) and water (10 mL). The combined organic layersare dried over sodium sulfate, filtered and concentrated to give a crudethat is purified by column chromatography (silica gel, eluent:cyclohexane:ethyl acetate:methanol, 4:1:0 to 0:9:1, v/v/v) to afford{1-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester as an orange solid (35 mg, 33% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.53 (d, J=2.7 Hz, 1H), 8.19 (dd,J=0.7, 9.0 Hz, 1H), 7.61 (dd, J=0.7, 2.7 Hz, 1H), 7.07 (d, J=9.0 Hz,1H), 6.75 (d, J=7.7 Hz, 1H), 4.27 (t, J=5.6 Hz, 2H), 4.02 (s, 3H), 3.20(m, 1H), 2.90 (m, 2H), 2.75 (t, J=5.6 Hz, 2H), 2.07 (m, 2H), 1.70 (m,2H), 1.37 (m, 11H).

MS m/z (+ESI): 403.2 [M+H]⁺.

Alternative Preparation of methanesulfonic acid2-(tert-butoxycarbonylamino-piperidin-1-yl)-ethyl ester

Triethylamine (515 μL, 3.69 mmol, 0.95 eq) is added at 0° C. to astirred solution of [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acidtert-butyl ester (1.0 g, 3.89 mmol, 1.0 eq) in dichloromethane (40 mL),followed by the dropwise addition of methanesulfonyl chloride (286 μL,3.69 mmol, 0.95 eq). After 2 hours stirring at 0° C., the reactionmixture is extracted with dichloromethane (3×30 mL) and water (30 mL).The combined organic layers are dried over sodium sulfate, filtered andconcentrated to afford methanesulfonic acid2-(tert-butoxycarbonylamino-piperidin-1-yl)-ethyl ester as an off-whitesemisolid (961 mg, 61% yield, 80% ELSD purity) that is directly engagedin the next step.

Preparation of{1-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester

Sodium hydride (55% purity, 9 mg, 0.22 mmol, 1.5 eq) is added at roomtemperature to a stirred solution of 6-methoxy-[1,5]naphthyridin-3-ol(42 mg, 0.22 mmol, 1.0 eq) in N,N-dimethylformamide (5 mL), followed bymethanesulfonic acid 2-(4-tert-butoxycarbonylamino-piperidin-1-yl)-ethylester (102 mg, 0.22 mmol, 1.0 eq). The reaction mixture is irradiated bymicrowaves at 110° C. for 10 minutes, then solvent is evaporated, andthe residue is extracted with ethyl acetate (3×10 mL) and water (10 mL).The combined organic layers are dried over sodium sulfate, filtered andconcentrated to give a residue that is purified by column chromatography(silica gel, eluent: cyclohexane:ethyl acetate:methanol, 1:1:0 to 0:9:1,v/v/v) to afford{1-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester as an orange solid (27 mg, 29% yield).

Preparation of7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as an off-white lyophilizated powderfollowing Scheme 1 and in analogy to Example 1 using{1-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester and7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid asstarting materials.

MS m/z (+ESI): 528.2 [M+H]⁺.

Example 17 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicacid {1-[2-(7-methoxy-quinolin-2-yloxy)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as an off-white lyophilizated powderfollowing Scheme 1 and in analogy to Examples 1 and 12 using2-chloro-7-methoxy-quinoline,[1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid asstarting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 11.00 (s, 1H), 8.14 (d, J=8.6 Hz, 1H),8.02 (d, J=8.1 Hz, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H),7.59 (d, J=7.8 Hz, 1H), 7.17 (d, J=2.5 Hz, 1H), 7.06 (dd, J=2.5, 8.8 Hz,1H), 6.84 (d, J=8.8 Hz, 1H), 4.53 (t, J=5.9 Hz, 2H), 3.89 (s, 3H), 3.79(m, 1H), 3.64 (s, 2H), 2.94 (m, 2H), 2.81 (t, J=5.9 Hz, 2H), 2.30 (m,2H), 1.88 (m, 2H), 1.55 (m, 2H).

MS m/z (+EST): 494.2 [M+H]⁺.

Example 18 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-methoxy-[1,5]naphthyridin-2-yloxy)-ethyl]-piperidin-4-yl}-amidePreparation of 2,7-dimethoxy-[1,5]naphthyridine

Potassium carbonate (13.84 g, 100.1 mmol, 2.0 eq) is added at roomtemperature to a stirred solution of 6-methoxy-[1,5]naphthyridin-3-ol(9.8 g, 50.06 mmol, 1.0 eq) in acetone (300 mL), followed by iodomethane(3.74 mL, 60.1 mmol, 1.2 eq). After 4 hours stirring under refluxconditions, the solid is removed by filtration and the filtrate isconcentrated to give a residue that is extracted with ethyl acetate(3×100 mL) and water (100 mL). The combined organic layers are washedwith brine, dried over sodium sulfate, filtered and concentrated to givea residue that is purified by column chromatography (silica gel, eluent:petroleum ether:ethyl acetate, 6:1, v/v) to afford2,7-dimethoxy-[1,5]naphthyridine as a yellow solid (5.2 g, 52% yield).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 8.53 (d, J=2.4 Hz, 1H), 8.19 (d, J=8.8Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 4.07 (s, 3H),3.97 (s, 3H).

MS m/z (+ESI): 191.3 [M+H]⁺.

Preparation of 2-chloro-7-methoxy-[1,5]naphthyridine

A mixture of 2,7-dimethoxy-[1,5]naphthyridine (5.0 g, 26.29 mmol, 1.0eq) and phosphorus oxychloride (4.9 mL, 52.58 mmol, 2.0 eq) inN,N-dimethylformamide (100 mL) is stirred at 0° C. for 1 hour then at80° C. for 1 hour. The reaction mixture is cooled to 0° C., quenchedwith 10 mL of saturated sodium acetate aqueous solution and then stirredat 30° C. for 30 minutes. The mixture is extracted with ethyl acetate(3×60 mL). The combined organic layers are dried over sodium sulfate,filtered and concentrated to give a crude that is purified by columnchromatography (silica gel, eluent: ethyl acetate:petroleum ether, 1:6,v/v) to afford 2-chloro-7-methoxy-[1,5]naphthyridine as a yellow solid(3.3 g, 64% yield).

¹H-NMR (400 MHz, Acetone-d6) δ ppm: 8.70 (d, J=2.8 Hz, 1H), 8.34 (d,J=8.4 Hz, 1H), 7.63 (d, J=2.8 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 4.06 (s,3H).

MS m/z (+ESI): 195.2 [M+H]⁺.

Preparation of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-methoxy-[1,5]naphthyridin-2-yloxy)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as an off-white lyophilizated powderfollowing Scheme 1 and in analogy to Example 1 using2-chloro-7-methoxy-[1,5]naphthyridine,[1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as startingmaterials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.65 (s, 1H), 8.54 (d, J=2.8 Hz, 1H),8.14-8.23 (m, 2H), 7.57 (d, J=2.8 Hz, 1H), 7.38-7.45 (m, 3H), 7.08 (d,J=9.0 Hz, 1H), 4.55 (t, J=5.9 Hz, 2H), 3.96 (s, 3H), 3.77 (m, 1H), 3.50(s, 2H), 3.02 (m, 2H), 2.80 (t, J=5.9 Hz, 2H), 2.18 (m, 2H), 1.79 (m,2H), 1.58 (m, 2H).

MS m/z (+ESI): 494.2 [M+H]⁺.

Example 19 7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid{1-[2-(7-methoxy-[1,5]naphthyridin-2-yloxy)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as an off-white lyophilizated powderfollowing Scheme 1 and in analogy to Example 1 using2-chloro-7-methoxy-[1,5]naphthyridine,[1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid asstarting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.70 (s, 1H), 8.54 (d, J=2.7 Hz, 1H),8.35 (d, J=7.8 Hz, 1H), 8.19 (d, J=9.0 Hz, 1H), 7.56 (d, J=2.7 Hz, 1H),7.49 (s, 1H), 7.07 (d, J=9.0 Hz, 1H), 6.95 (s, 1H), 4.54 (t, J=5.8 Hz,2H), 3.96 (s, 3H), 3.72 (m, 1H), 3.50 (s, 2H), 2.98 (m, 2H), 2.78 (t,J=5.8 Hz, 2H), 2.20 (m, 2H), 1.80 (m, 2H), 1.50 (m, 2H).

MS m/z (+ESI): 528.2 [M+H]⁺.

Example 20 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicacid {1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as an off-white lyophilizated powderfollowing Scheme 1 and in analogy to Example 1 using2-chloro-7-methoxy-quinoxaline,[1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid asstarting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 11.00 (s, 1H), 8.42 (s, 1H), 8.01 (d,J=8.1 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.89 (d, J=8.9 Hz, 1H), 7.58 (d,J=7.8 Hz, 1H), 7.22-7.28 (m, 2H), 4.56 (t, J=5.7 Hz, 2H), 3.93 (s, 3H),3.78 (m, 1H), 3.64 (s, 2H), 2.93 (m, 2H), 2.81 (t, J=5.7 Hz, 2H), 2.28(m, 2H), 1.84 (m, 2H), 1.52 (m, 2H).

MS m/z (+ESI): 495.2 [M+H]⁺.

Example 21 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as a white amorphous lyophilizated solidfollowing Scheme 1 and in analogy to Example 1 using2-chloro-quinoxaline, [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acidtert-butyl ester and3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as startingmaterials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.65 (s, 1H), 8.62 (s, 1H), 8.21 (d,J=7.8 Hz, 1H), 8.02 (dd, J=1.3, 8.2 Hz, 1H), 7.84 (m, 1H), 7.77 (m, 1H),7.65 (m, 1H), 7.42 (m, 3H), 4.58 (t, J=5.8 Hz, 2H), 3.75 (m, 1H), 3.50(s, 2H), 3.02 (m, 2H), 2.81 (t, J=5.8 Hz, 2H), 2.17 (m, 2H), 1.78 (m,2H), 1.55 (m, 2H).

MS m/z (+ESI): 464.2 [M+H]⁺.

Example 22 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-azetidin-3-yl}-amide

The title compound is prepared as an off-white lyophilizated powderfollowing Scheme 1 and in analogy to Example 1 using2-chloro-7-methoxy-quinoxaline, 2-bromo-ethanol, azetidin-3-yl-carbamicacid tert-butyl ester and3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as startingmaterials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.74 (s, 1H), 8.82 (d, J=7.0 Hz, 1H),8.41 (s, 1H), 7.89 (d, J=9.0 Hz, 1H), 7.40-7.45 (m, 3H), 7.20-7.30 (m,2H), 4.44-4.55 (m, 3H), 3.92 (s, 3H), 3.78 (m, 2H), 3.50 (s, 2H), 3.35(m, 2H), 3.00 (m, 2H).

MS m/z (+ESI): 466.1 [M+H]⁺.

Example 23 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[3-(7-methoxy-quinoxalin-2-yloxy)-propyl]-pyrrolidin-3-ylamide

The title compound is prepared as a white solid following Scheme 1 andin analogy to Example 1 using 2-chloro-7-methoxy-quinoxaline,3-bromo-propan-1-ol, pyrrolidin-3-yl-carbamic acid tert-butyl ester and3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as startingmaterials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.67 (s, 1H), 8.47 (d, J=6.8 Hz, 1H),8.40 (s, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.46 (m, 2H), 7.38 (d, J=8.0 Hz,1H), 7.25 (m, 2H), 4.47 (t, J=6.8 Hz, 2H), 4.39 (m, 1H), 3.92 (m, 3H),3.50 (s, 2H), 2.86 (m, 2H), 2.45-2.70 (m, 4H), 2.15 (m, 1H), 2.00 (m,2H), 1.78 (m, 1H).

MS m/z (+ESI): 480.2 [M+H]⁺.

Example 24 7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid{1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-ylmethyl}-amide

The title compound is prepared as an off-white solid following Scheme 1and in analogy to Example 1 using 2-chloro-7-methoxy-quinoxaline,2-bromo-ethanol, piperidin-4-ylmethyl-carbamic acid tert-butyl ester and7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid asstarting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.72 (s, 1H), 8.44 (t, J=5.8 Hz, 1H),8.41 (s, 1H), 7.89 (d, J=9.0 Hz, 1H), 7.49 (s, 1H), 7.25 (m, 2H), 6.97(s, 1H), 4.55 (t, J=5.8 Hz, 2H), 3.92 (s, 3H), 3.52 (s, 2H), 3.09 (t,J=6.2 Hz, 2H), 2.98 (m, 2H), 2.78 (t, J=5.8 Hz, 2H), 2.07 (m, 2H), 1.70(m, 2H), 1.53 (m, 1H), 1.22 (m, 2H).

MS m/z (+ESI): 542.3 [M+H]⁺.

Example 256-[({1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-methyl-amino)-methyl]-4H-benzo[1,4]thiazin-3-onePreparation of6-({1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]thiazin-3-one

The title compound is prepared as a yellow viscous oil following Scheme1 and in analogy to Example 9 using 2-chloro-7-methoxy-quinoxaline,[1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde as startingmaterials.

MS m/z (+ESI): 480.2 [M+H]⁺.

Preparation of6-[({1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-methyl-amino)-methyl]-4H-benzo[1,4]thiazin-3-one

Paraformaldehyde (29 mg, 0.10 mmol, 1.0 eq) is added at room temperatureto a stirred solution of6-({1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]thiazin-3-one(50 mg, 0.10 mmol, 1.0 eq) in 1,2-dichloroethane (2 mL) and methanol(0.5 mL), followed by acetic acid (7 μL, 0.12 mmol, 1.3 eq) and sodiumcyanoborohydride (9 mg, 0.12 mmol, 1.3 eq). After 15 hours stirring atroom temperature, the reaction mixture is extracted with dichloromethane(3×5 mL) and a saturated sodium hydrogen carbonate aqueous solution (5mL). The combined organic layers are dried over sodium sulfate, filteredand concentrated to give a residue that is purified by preparative HPLCto afford6-[({1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-methyl-amino)-methyl]-4H-benzo[1,4]thiazin-3-oneas a light brown viscous oil (11 mg, 21% yield).

MS m/z (+ESI): 494.3 [M+H]⁺.

Example 26 5-thiophen-2-yl-isoxazole-3-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-pyrrolidin-3-ylmethyl}-amide

The title compound is prepared as an orange semi-solid following Scheme1 and in analogy to Example 1 using 2-chloro-7-methoxy-quinoxaline,2-bromo-ethanol, pyrrolidin-3-ylmethyl-carbamic acid tert-butyl esterand 5-thiophen-2-yl-isoxazole-3-carboxylic acid as starting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.77 (t, J=5.6 Hz, 1H), 8.38 (s, 1H),7.86 (m, 2H), 7.75 (dd, J=1.1, 3.6 Hz, 1H), 7.23 (m, 3H), 7.10 (s, 1H),4.55 (t, J=5.8 Hz, 2H), 3.92 (s, 3H), 3.27 (t, J=6.2 Hz, 2H), 2.91 (m,2H), 2.70 (m, 2H), 2.40-2.65 (m, 3H), 1.90 (m, 1H), 1.52 (m, 1H).

MS m/z (+ESI): 480.2 [M+H]⁺.

Example 27 7-chloro-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[3-(7-methoxy-quinoxalin-2-yloxy)-propyl]-pyrrolidin-3-ylmethyl}-amide

The title compound is prepared as a light yellow lyophilizated powderfollowing Scheme 1 and in analogy to Example 1 using2-chloro-7-methoxy-quinoxaline, 3-bromo-propan-1-ol,pyrrolidin-3-ylmethyl-carbamic acid tert-butyl ester and7-chloro-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as startingmaterials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.38 (s, 1H), 8.17 (t, J=5.5 Hz, 1H),7.88 (d, J=9.0 Hz, 1H), 7.24 (m, 2H), 6.91 (s, 1H), 6.55 (s, 1H), 6.28(br, 1H), 4.49 (t, J=6.6 Hz, 2H), 3.92 (s, 3H), 3.48 (m, 2H), 3.18 (m,2H), 2.99 (m, 2H), 2.33-2.70 (m, 7H), 2.00 (m, 2H), 1.90 (m, 1H), 1.50(m, 1H).

MS m/z (+ESI): 528.3 [M+H]⁺.

Example 28 6-methoxy-quinoline-3-carboxylic acidtrans-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-cyclohexylmethylester Preparation oftrans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid

trans-4-Amino-cyclohexanecarboxylic acid (10.0 g, 69.8 mmol, 1.0 eq) issuspended in dioxane (100 mL) and water (200 mL) and sodium hydrogencarbonate (7.0 g, 83.8 mmol, 1.2 eq) is added at room temperature,followed by a solution of di-tert-butyl-dicarbonate (21.3 g, 97.8 mmol,1.4 eq) in dioxane (100 mL). After 24 hours stirring at roomtemperature, dioxane is evaporated and the pH of the aqueous residue isadjusted to 3 by the addition of a 1N hydrochloric acid aqueous solutionand extracted with ethyl acetate (3×50 mL). The combined organic layersare dried over sodium sulfate, filtered and concentrated to affordtrans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid as a whitesolid (16.1 g, 93% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 12.05 (br, 1H), 6.72 (d, J=7.8 Hz, 1H),3.15 (m, 1H), 2.08 (m, 1H), 1.75-1.92 (m, 4H), 1.37 (s, 9H), 1.05-1.35(m, 4H).

MS m/z (+ESI): 266.2 [M+Na]⁺.

Preparation of trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylicacid methyl ester

Potassium carbonate (877 mg, 6.34 mmol, 1.05 eq) is added at roomtemperature to a stirred solution oftrans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (1.50 g,6.04 mmol, 1.0 eq) in N,N-dimethylformamide (30 mL), followed by methyliodide (395 μL, 6.34 mmol, 1.05 eq). After 5 hours stirring at roomtemperature, solvent is evaporated and the residue is extracted withethyl acetate (3×30 mL) and water (30 mL). The combined organic layersare washed with brine (30 mL), dried over sodium sulfate, filtered andconcentrated to affordtrans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid methyl esteras a yellow solid (1.60 g, 98% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 6.72 (d, J=7.8 Hz, 1H), 3.58 (s, 3H),3.15 (m, 1H), 2.10 (m, 1H), 1.75-1.92 (m, 4H), 1.37 (s, 9H), 1.07-1.36(m, 4H).

MS m/z (+ESI): 280.2 [M+Na]⁺.

Preparation of trans-4-amino-cyclohexanecarboxylic acid methyl ester

Trifluoroacetic acid (13.47 mL, 19.94 mmol, 15.0 eq) is added at 0° C.to a stirred solution oftrans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid methyl ester(3.53 g, 11.66 mmol, 1.0 eq) in dichloromethane (100 mL). After 15 hoursstirring at room temperature, the reaction mixture is extracted withdichloromethane (3×50 mL) and water (50 mL) and the pH is adjusted to 12by the addition of a 1N sodium hydroxide aqueous solution. The combinedorganic layers are dried over sodium sulfate, filtered and concentratedto afford trans-4-amino-cyclohexanecarboxylic acid methyl ester as ayellow oil (1.53 g, 79% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 3.58 (s, 3H), 2.48 (m, 1H), 2.18 (m,1H), 1.72-1.90 (m, 4H), 1.35 (qd, J=3.4, 13.2 Hz, 2H), 1.02 (qd, J=3.4,13.2 Hz, 2H).

MS m/z (+ESI): 158.2 [M+H]⁺.

Preparation oftrans-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-cyclohexanecarboxylicacid methyl ester

3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (116 mg, 0.50mmol, 1.0 eq) is added at room temperature to a stirred solution oftrans-4-amino-cyclohexanecarboxylic acid methyl ester (80 mg, 0.50 mmol,1.0 eq) in N,N-dimethylformamide (4 mL), followed by1-hydroxybenzotriazole (74 mg, 0.55 mmol, 1.1 eq),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (107 mg,0.56 mmol, 1.15 eq) and N,N-diisopropylethylamine (192 μL, 1.12 mmol,2.25 eq). After 15 hours stirring at room temperature, solvent isevaporated and the residue is extracted with dichloromethane (3×10 mL)and water (10 mL). The combined organic layers are dried over sodiumsulfate, filtered and concentrated to affordtrans-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-cyclohexanecarboxylicacid methyl ester as an off-white solid (127 mg, 66% yield).

MS m/z (+ESI): 349.2 [M+H]⁺.

Preparation of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid(trans-4-hydroxymethyl-cyclohexyl)-amide

Lithium aluminium hydride (1.0 M solution in tetrahydrofuran, 0.66 mL,0.66 mmol, 2.0 eq) is added at 0° C. to a stirred solution oftrans-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-cyclohexanecarboxylicacid methyl ester (127 mg, 0.33 mmol, 1.0 eq) in tetrahydrofuran (2 mL).After 1 hour stirring at 0° C., the reaction mixture is cautiouslyquenched with ice-water (3 mL). Tetrahydrofuran is evaporated and thecrude is extracted with ethyl acetate (3×10 mL) and water (10 mL). Thecombined organic layers are dried over sodium sulfate, filtered andconcentrated to afford3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid(trans-4-hydroxymethyl-cyclohexyl)-amide as a yellow solid (47 mg, 40%yield).

MS m/z (+ESI): 321.2 [M+H]⁺.

Preparation of 6-methoxy-quinoline-3-carboxylic acidtrans-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-cyclohexylmethylester

6-Methoxy-quinoline-3-carboxylic acid (27 mg, 0.13 mmol, 1.0 eq) isadded at room temperature to a stirred solution of3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid(trans-4-hydroxymethyl-cyclohexyl)-amide (47 mg, 0.13 mmol, 1.0 eq) inN,N-dimethylformamide (2 mL), followed byN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (28 mg,0.15 mmol, 1.10 eq) and 4-(dimethylamino)pyridine (24 mg, 0.20 mmol,1.50 eq). After 15 hours stirring at room temperature, solvent isevaporated and the residue is extracted with dichloromethane (3×10 mL)and water (10 mL). The combined organic layers are dried over sodiumsulfate, filtered and concentrated to give a residue that is purified bypreparative HPLC to afford 6-methoxy-quinoline-3-carboxylic acidtrans-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-cyclohexylmethylester as a white solid (7 mg, 10% yield).

MS m/z (+ESI): 506.4 [M+H]⁺.

Example 29 6-methoxy-[1,5]naphthyridine-3-carboxylic acidtrans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexylmethylester Preparation oftrans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid methyl ester

2,3-Dihydro-benzo[1,4]dioxine-6-carbaldehyde (198 mg, 1.21 mmol, 1.0 eq)is added at room temperature to a stirred solution oftrans-4-amino-cyclohexanecarboxylic acid methyl ester (200 mg, 1.21mmol, 1.0 eq) in 1,2-dichloroethane (8 mL) and methanol (2 mL), followedby acetic acid (80 μL, 1.39 mmol, 1.15 eq) and sodium cyanoborohydride(99 mg, 1.57 mmol, 1.3 eq). After 15 hours stirring at room temperature,the reaction mixture is extracted with dichloromethane (3×20 mL) and asaturated sodium hydrogen carbonate aqueous solution (20 mL). Thecombined organic layers are dried over sodium sulfate, filtered andconcentrated to affordtrans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid methyl ester as an orange oil (359 mg, 92% yield).

MS m/z (+ESI): 306.2 [M+H]⁺.

Preparation of{trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexyl}-methanol

Lithium aluminium hydride (1.0 M solution in tetrahydrofuran, 2.20 mL,2.20 mmol, 2.0 eq) is added at 0° C. to a stirred solution oftrans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid methyl ester (355 mg, 1.10 mmol, 1.0 eq) in tetrahydrofuran (30mL). After 2 hours stirring at 0° C., the reaction mixture is cautiouslyquenched with ice-water (6 mL). Tetrahydrofuran is evaporated and thecrude is extracted with ethyl acetate (3×50 mL) and water (50 mL). Thecombined organic layers are dried over sodium sulfate, filtered andconcentrated to afford{trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexyl}-methanolas an orange oil (322 mg, 99% yield).

MS m/z (+ESI): 278.3 [M+H]⁺.

Preparation of 6-methoxy-[1,5]naphthyridine-3-carboxylic acidtrans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexylmethylester

6-Methoxy-[1,5]naphthyridine-3-carboxylic acid (100 mg, 0.44 mmol, 1.0eq) is added at room temperature to a stirred solution oftrans-{4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexyl}-methanol(129 mg, 0.44 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed byN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (93 mg,0.48 mmol, 1.10 eq) and 4-(dimethylamino)pyridine (81 mg, 0.66 mmol,1.50 eq). After 15 hours stirring at room temperature, solvent isevaporated and the residue is extracted with dichloromethane (3×10 mL)and water (10 mL). The combined organic layers are dried over sodiumsulfate, filtered and concentrated to give a residue that is purified bypreparative HPLC to afford 6-methoxy-[1,5]naphthyridine-3-carboxylicacidtrans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexylmethylester as an off-white semisolid (33 mg, 15% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 9.22 (d, J=2.0 Hz, 1H), 8.60 (dd,J=0.7, 1.4 Hz, 1H), 8.37 (dd, J=0.7, 9.1 Hz, 1H), 8.29 (s, 1H), 7.42 (d,J=9.1 Hz, 1H), 6.85 (m, 3H), 4.20 (m, 6H), 4.07 (s, 3H), 3.73 (s, 2H),2.43 (m, 1H), 2.02 (m, 2H), 1.87 (m, 2H), 1.78 (m, 1H), 1.05-1.25 (m,4H).

MS m/z (+ESI): 464.4 [M+H]⁺.

Example 30 6-methoxy-[1,5]naphthyridine-3-carboxylic acidtrans-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbonyl)-amino]-cyclohexylmethylester

The title compound is prepared as a light brown semisolid followingScheme 2 and in analogy to Example 28 using3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxylic acid,trans-4-amino-cyclohexanecarboxylic acid methyl ester and6-methoxy-[1,5]naphthyridine-3-carboxylic acid as starting materials.

MS m/z (+ESI): 492.4 [M+H]⁺.

Example 31 6-methoxy-[1,5]naphthyridine-3-carboxylic acidtrans-4-[2-(thiophen-2-ylsulfanyl)-ethylamino]-cyclohexylmethyl esterPreparation of 2-(2-bromo-ethylsulfanyl)-thiophene

Potassium carbonate (2.50 g, 18.07 mmol, 2.1 eq) is added at roomtemperature to a stirred solution of thiophene-2-thiol (813 μL, 8.61mmol, 1.0 eq) in 1,2-dibromoethane (10 mL) and the resulting mixture isstirred at 78° C. for 3 hours. Then potassium carbonate is removed byfiltration and the mother liquid is concentrated to give a crude that ispurified by column chromatography (silica gel, eluent: cyclohexane 100%)to afford 2-(2-bromo-ethylsulfanyl)-thiophene as a light yellow oil(1.86 g, 95% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 7.68 (dd, J=1.2, 5.3 Hz, 1H), 7.27 (dd,J=1.2, 3.5 Hz, 1H), 7.09 (dd, J=3.5, 5.3 Hz, 1H), 3.56 (m, 2H), 3.19 (m,2H).

Preparation oftrans-4-[2-(thiophen-2-ylsulfanyl)-ethylamino]-cyclohexanecarboxylicacid methyl ester

2-(2-Bromo-ethylsulfanyl)-thiophene (275 mg, 1.21 mmol, 1.0 eq) is addedat room temperature to a stirred solution oftrans-4-amino-cyclohexanecarboxylic acid methyl ester (200 mg, 1.21mmol, 1.0 eq) in acetonitrile (6 mL). After 15 hours stirring at 100°C., the reaction mixture is evaporated to affordtrans-4-[2-(thiophen-2-ylsulfanyl)-ethylamino]-cyclohexanecarboxylicacid methyl ester as an off-white oil (261 mg, 68% yield).

MS m/z (+EST): 300.2 [M+H]⁺.

Preparation of 6-methoxy-[1,5]naphthyridine-3-carboxylic acidtrans-4-[2-(thiophen-2-ylsulfanyl)-ethylamino]-cyclohexylmethyl ester

The title compound is prepared as an off-white viscous oil followingScheme 2 and in analogy to Example 28 using6-methoxy-[1,5]naphthyridine-3-carboxylic acid andtrans-4-[2-(thiophen-2-ylsulfanyl)-ethylamine]-cyclohexanecarboxylicacid methyl ester as starting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 9.23 (d, J=2.0 Hz, 1H), 8.59 (dd,J=0.7, 2.0 Hz, 1H), 8.38 (dd, J=0.7, 9.1 Hz, 1H), 8.25 (s, 1H), 7.62(dd, J=1.2, 5.3 Hz, 1H), 7.42 (d, J=9.3 Hz, 1H), 7.20 (dd, J=1.2, 3.5Hz, 1H), 7.05 (dd, J=3.5, 5.3 Hz, 1H), 4.20 (d, J=6.3 Hz, 2H), 4.06 (s,3H), 2.75-2.90 (m, 4H), 2.42 (m, 1H), 1.72-1.97 (m, 5H), 0.92-1.18 (m,4H).

MS m/z (+ESI): 458.3 [M+H]⁺.

Example 32 6-methoxy-quinoline-3-carboxylic acidtrans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-amino]-cyclohexylmethylester Preparation oftrans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-amino]-cyclohexanecarboxylicacid methyl ester

Potassium tert-butylate (35 mg, 0.31 mmol, 1.0 eq) is added at roomtemperature to a stirred solution oftrans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid methyl ester (100 mg, 0.31 mmol, 1.0 eq) in N,N-dimethylformamide(4 mL), followed by methyl iodide (10 μL, 0.16 mmol, 0.5 eq). After 15hours stirring at room temperature methyl iodide (10 μL, 0.16 mmol, 0.5eq) is added again. After 4 hours stirring at room temperature, solventis evaporated and the residue is extracted with ethyl acetate (3×5 mL)and water (5 mL). The combined organic layers are washed with brine (5mL), dried over sodium sulfate, filtered and concentrated to affordtrans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-amino]-cyclohexanecarboxylicacid methyl ester as a brown oil (1.60 g, 98% yield).

MS m/z (+ESI): 320.3 [M+H]⁺, 334.3 [M+Na]⁺.

Preparation of 6-methoxy-quinoline-3-carboxylic acidtrans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-amino]-cyclohexylmethylester

The title compound is prepared as a yellow oil following Scheme 2 and inanalogy to Example 28 using 6-methoxy-quinoline-3-carboxylic acid andtrans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-amino]-cyclohexanecarboxylicacid methyl ester as starting materials.

MS m/z (+ESI): 477.4 [M+H]⁺.

Example 33 6-methoxy-quinoline-3-carboxylic acidtrans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexylmethylester

The title compound is prepared as an off-white semisolid (24 mg, 26%yield) following Scheme 2 and in analogy to Example 28 using6-methoxy-quinoline-3-carboxylic acid (40 mg, 0.19 mmol, 1.0 eq) and{trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexyl}-methanol(55 mg, 0.19 mmol, 1.0 eq) as starting materials.

Alternative Procedure Preparation of 6-methoxy-quinoline-3-carboxylicacid trans-4-tert-butoxycarbonylamino-cyclohexylmethyl ester

trans-(4-Hydroxymethyl-cyclohexyl)-carbamic acid tert-butyl ester (480mg, 2.46 mmol, 1.0 eq) is added at room temperature to a stirredsolution of 6-methoxy-quinoline-3-carboxylic acid (564 mg, 2.46 mmol,1.0 eq) in dichloromethane (15 mL), followed by 1-hydroxybenzotriazole(532 mg, 3.94 mmol, 1.6 eq),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.04 g,5.41 mmol, 2.2 eq) and triethylamine (754 μL, 5.41 mmol, 2.2 eq). After15 hours stirring at 30° C., solvent is evaporated and the residue ispurified by column chromatography (silica gel, eluent: petroleumether:ethyl acetate, 4:1, v/v) to afford6-methoxy-quinoline-3-carboxylic acidtrans-4-tert-butoxycarbonylamino-cyclohexylmethyl ester as a whitepowder (787 mg, 77% yield).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 9.29 (s, 1H), 8.74 (s, 1H), 8.10 (d,J=8.8 Hz, 1H), 7.50 (dd, J=2.8, 8.8 Hz, 1H), 7.20 (d, J=2.8 Hz, 1H),4.24 (d, J=6.4 Hz, 2H), 3.97 (s, 3H), 3.39-3.48 (m, 1H), 2.07-2.11 (m,2H), 1.92-1.96 (m, 2H), 1.61-1.80 (m, 1H), 1.45 (s, 9H), 1.11-1.25 (m,4H).

MS m/z (+ESI): 415.2 [M+H]⁺.

Preparation of the trifluoroacetic acid salt of6-methoxy-quinoline-3-carboxylic acid trans-4-amino-cyclohexylmethylester

Trifluoroacetic acid (1.45 mL, 18.82 mmol, 10.0 eq) is added at 0° C. toa stirred solution of 6-methoxy-quinoline-3-carboxylic acidtrans-4-tert-butoxycarbonylamino-cyclohexylmethyl ester (780 mg, 1.88mmol, 1.0 eq) in dichloromethane (10 mL). After 5 hours stirring at roomtemperature, the reaction mixture is concentrated to give a crudeproduct that is triturated in diethyl ether to afford thetrifluoroacetic acid salt of 6-methoxy-quinoline-3-carboxylic acidtrans-4-amino-cyclohexylmethyl ester as an off-white powder (800 mg, 98%yield).

¹H-NMR (400 MHz, DMSO-d6, D₂O) δ ppm: 9.11 (s, 1H), 8.89 (s, 1H), 7.98(d, J=8.0 Hz, 1H), 7.56 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 4.18 (d, J=5.6Hz), 3.82 (s, 3H), 2.90-2.97 (m, 1H), 1.85-1.96 (m, 4H), 1.73-7.78 (m,1H), 1.14-1.32 (m, 4H).

MS m/z (+ESI): 315.2 [M+H]⁺.

Preparation of 6-methoxy-quinoline-3-carboxylic acidtrans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexylmethylester

2,3-Dihydro-benzo[1,4]dioxine-6-carbaldehyde (188 mg, 1.14 mmol, 1.8 eq)is added at room temperature to a stirred solution of thetrifluoroacetic acid salt of 6-methoxy-quinoline-3-carboxylic acidtrans-4-amino-cyclohexylmethyl ester (200 mg, 0.64 mmol, 1.0 eq) in1,2-dichloroethane (10 mL), followed by sodium triacetoxyborohydride(1.35 g, 6.36 mmol, 10.0 eq). After 18 hours stirring at roomtemperature, the reaction mixture is extracted with dichloromethane(3×10 mL) and a saturated sodium hydrogen carbonate aqueous solution (10mL). The combined organic layers are dried over sodium sulfate, filteredand concentrated to give a residue that is purified by preparative HPLCto afford 6-methoxy-quinoline-3-carboxylic acidtrans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexylmethylester as a white powder (123 mg, 40% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 9.14 (s, 1H), 8.87 (s, 1H), 8.00 (d,J=9.2 Hz, 1H), 7.64 (d, J=2.8 Hz, 1H), 7.54 (dd, J=2.8, 9.2 Hz, 1H),6.87 (s, 1H), 6.77 (m, 2H), 4.17 (m, 6H), 3.90 (s, 3H), 3.72 (s, 2H),2.48 (m, 1H), 1.84-2.02 (m, 4H), 1.73 (m, 1H), 1.12 (m, 4H).

MS m/z (+ESI): 463.2 [M+H]⁺.

Example 34 6-methoxy-quinoline-3-carboxylic acidtrans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-ethyl-amino]-cyclohexylmethylester

Ethyl iodide (51 μL, 0.63 mmol, 8.0 eq) is added at room temperature toa stirred solution of 6-methoxy-quinoline-3-carboxylic acidtrans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexylmethylester (37 mg, 0.08 mmol, 1.0 eq) in N,N-dimethylformamide (0.5 mL),followed by silver oxide (73 mg, 0.31 mmol, 4.0 eq). After 4 hoursstirring at room temperature, the reaction mixture is filtered throughdecalite and the mother liquid is concentrated to give a residue that ispurified by preparative HPLC to afford 6-methoxy-quinoline-3-carboxylicacidtrans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-ethyl-amino]-cyclohexylmethylester as an off-white lyophilizated solid (9 mg, 14% yield)

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 9.15 (s, 1H), 8.89 (s, 1H), 8.01 (d,J=9.2 Hz, 1H), 7.66 (d, J=2.8 Hz, 1H), 7.56 (dd, J=2.8, 9.2 Hz, 1H),6.81 (s, 1H), 6.76 (m, 2H), 4.17-4.21 (m, 6H), 3.93 (s, 3H), 3.47 (s,2H), 3.30 (m, 2H), 2.48 (m, 1H), 1.78-1.95 (m, 4H), 1.73 (m, 1H), 1.33(m, 2H), 1.08 (m, 2H), 0.93 (t, J=7.1 Hz, 3H).

MS m/z (+ESI): 491.4 ([M+H]⁺.

Example 35 5-thiophen-2-yl-isoxazole-3-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amidePreparation of 2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethanol

2-Mercaptoethanol (2.5 g, 32.06 mmol, 1.2 eq) is added at roomtemperature to a stirred solution of 2-chloro-7-methoxy-quinoxaline (5.2g, 26.72 mmol, 1.0 eq) in N,N-dimethylformamide (160 mL), followed bypotassium carbonate (7.4 g, 53.44 mol, 2.0 eq). After 15 hours stirringat room temperature, solvent is evaporated and the residue is extractedwith ethyl acetate (3×150 mL) and water (100 mL). The combined organiclayers are dried over sodium sulfate, filtered and concentrated to givea crude product that is purified by column chromatography (silica gel,eluent: ethyl acetate:hexane, 1:2, v/v) to afford2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethanol as a pale yellow solid(6.22 g, 99% yield).

¹H-NMR (400 MHz, DMSO-d6)

ppm: 8.57 (s, 1H), 7.84 (d, J=9.2 Hz, 1H), 7.28 (dd, J=2.4, 9.2 Hz, 1H),7.24 (d, J=2.4 Hz, 1H), 5.05 (m, 1H), 3.91 (s, 3H), 3.69 (m, 2H), 3.38(m, 2H).

MS m/z (+ESI): 236.9 [M+H]⁺.

Preparation of (7-methoxy-quinoxalin-2-ylsulfanyl)-acetaldehyde

Dess-Martin periodinane (10.8 g, 25.4 mmol, 2.0 eq) is added at 0° C. toa stirred solution of 2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethanol (3.0g, 12.7 mmol, 1.0 eq) in dichloromethane (100 mL). The reaction mixtureis stirred 0° C. for 30 minutes then at room temperature for 3 hours.Then a saturated sodium thiosulfate aqueous solution (50 mL) is added,followed by a saturated sodium hydrogen carbonate aqueous solution (50mL). The resulting mixture is stirred for 30 minutes, then extractedwith dichloromethane (3×100 mL). The combined organic layers are driedover sodium sulfate, filtered and concentrated to give a crude productthat is purified by column chromatography (silica gel, eluent: ethylacetate:hexane, 1:5, v/v) to afford(7-methoxy-quinoxalin-2-ylsulfanyl)-acetaldehyde as a yellow oil (2.22g, 75% yield).

¹H NMR (400 MHz, Acetone-d6)

ppm: 9.72 (s, 1H), 8.65 (s, 1H), 7.89 (d, J=9.2 Hz, 1H), 7.29 (dd,J=2.4, 9.2 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 4.15 (s, 2H), 3.99 (s, 3H).

MS m/z (+ESI): 235.1 [M+H]⁺.

Preparation of{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester

Piperidin-4-yl-carbamic acid tert-butyl ester (2.82 g, 14.09 mmol, 1.5eq) is added at room temperature to a stirred solution of(7-methoxy-quinoxalin-2-ylsulfanyl)-acetaldehyde (2.2 g, 9.39 mmol, 1.0eq) in 1,2-dichloroethane (80 mL), followed by sodiumtriacetoxyborohydride (3.98 g, 18.78 mmol, 2.0 eq). After 15 hoursstirring at room temperature, the reaction mixture is extracted withdichloromethane (3×60 mL) and a saturated sodium hydrogen carbonateaqueous solution (60 mL). The combined organic layers are dried oversodium sulfate, filtered and concentrated to give a crude product thatis purified by column chromatography (silica gel, eluent: ethylacetate:hexane, 1:1, v/v) to give a yellow solid that is furtherrecrystallized with ethyl acetate:hexane (1:6, v/v) to afford{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester as light yellow needles (2.6 g, 66% yield).

¹H-NMR (400 MHz, DMSO-d6)

ppm: 8.58 (s, 1H), 7.86 (d, J=9.2 Hz, 1H), 7.30 (dd, J=2.1, 9.6 Hz, 1H),7.24 (d, J=2.4 Hz, 1H), 6.71 (br, 1H), 3.91 (s, 3H), 3.42 (m, 2H), 3.20(m, 1H), 2.89 (m, 2H), 2.63 (m, 2H), 2.03 (m, 2H), 1.67 (m, 2H), 1.37(m, 2H), 1.30 (s, 9H).

MS m/z (+ESI): 419.0 [M+H]⁺.

Preparation of1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine

Trifluoroacetic acid (5.41 mL, 70.2 mmol, 15.0 eq) is added at 0° C. toa stirred solution of{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester (2.0 g, 4.68 mmol, 1.0 eq) in dichloromethane (200mL). After 15 hours stirring at room temperature, the reaction mixtureis extracted with dichloromethane (3×50 mL) and water (50 mL) and the pHvalue adjusted to 12 by the addition of a 1N sodium hydroxide aqueoussolution. The combined organic layers are dried over sodium sulfate,filtered and concentrated to afford1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine asan orange oil (1.40 g, 92% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.61 (s, 1H), 7.90 (d, J=9.1 Hz, 1H),7.34 (dd, J=2.8, 9.1 Hz, 1H), 7.28 (d, J=2.8 Hz, 1H), 3.94 (s, 3H), 3.44(t, J=7.0 Hz, 2H), 2.88 (m, 2H), 2.64 (t, J=7.0 Hz, 2H), 2.05 (m, 2H),1.68 (m, 2H), 1.48 (br, 1H), 1.22 (m, 2H).

MS m/z (+ESI): 319.3 [M+H]⁺.

Preparation of 5-thiophen-2-yl-isoxazole-3-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide

5-Thiophen-2-yl-isoxazole-3-carboxylic acid (43 mg, 0.22 mmol, 1.0 eq)is added at room temperature to a stirred solution of1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (70mg, 0.22 mmol, 1.0 eq) in N,N-dimethylformamide (5 mL), followed by1-hydroxybenzotriazole (32 mg, 0.24 mmol, 1.1 eq),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (47 mg,0.25 mmol, 1.15 eq) and N,N-diisopropylethylamine (83 μL, 0.48 mmol,2.25 eq). After 15 hours stirring at room temperature, solvent isevaporated and the residue is extracted with dichloromethane (3×10 mL)and water (10 mL). The combined organic layers are dried over sodiumsulfate, filtered and concentrated to give a residue that is purified bypreparative HPLC to afford 5-thiophen-2-yl-isoxazole-3-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amideas an orange solid (15 mg, 13% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.73 (d, J=8.1 Hz, 1H), 8.62 (s, 1H),7.88 (m, 2H), 7.79 (d, J=1.1 Hz, 1H), 7.34 (dd, J=2.8, 9.1 Hz, 1H), 7.28(m, 2H), 7.19 (s, 1H), 3.94 (s, 3H), 3.78 (m, 1H), 3.48 (t, J=7.0 Hz,2H), 3.01 (m, 2H), 2.70 (t, J=7.0 Hz, 2H), 2.12 (m, 2H), 1.78 (m, 2H),1.62 (m, 2H).

MS m/z (+ESI): 496.2 [M+H]⁺.

Example 36 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as an off-white solid (42 mg, 38% yield)following Scheme 3 and in analogy to Example 35 using3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (42 mg, 0.22mmol 1.0 eq) and1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (70mg, 0.22 mmol, 1.0 eq) as starting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.81 (s, 1H), 8.62 (s, 1H), 8.16 (d,J=7.8 Hz, 1H), 7.90 (d, J=9.1 Hz, 1H), 7.28-7.45 (m, 4H), 6.98 (d, J=8.5Hz, 1H), 4.63 (s, 2H), 3.94 (s, 3H), 3.77 (m, 1H), 3.48 (t, J=7.0 Hz,2H), 3.01 (m, 2H), 2.72 (t, J=7.0 Hz, 2H), 2.14 (m, 2H), 1.78 (m, 2H),1.57 (m, 2H).

MS m/z (+ESI): 494.2 [M+H]⁺.

Example 37 7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as an off-white solid (42 mg, 60% yield)following Scheme 3 and in analogy to Example 35 using7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (31mg, 0.12 mmol 1.0 eq) and1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (40mg, 0.12 mmol, 1.0 eq) as starting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.73 (s, 1H), 8.62 (s, 1H), 8.38 (d,J=7.8 Hz, 1H), 7.90 (d, J=9.1 Hz, 1H), 7.50 (s, 1H), 7.35 (dd, J=2.8,9.1 Hz, 1H), 7.28 (d, J=2.8 Hz, 1H), 6.94 (s, 1H), 3.94 (s, 3H), 3.75(m, 1H), 3.51 (s, 2H), 3.48 (t, J=7.0 Hz, 2H), 3.01 (m, 2H), 2.72 (m,2H), 2.21 (m, 2H), 1.81 (m, 2H), 1.50 (m, 2H).

MS m/z (+ESI): 544.2 [M+H]⁺.

Example 38{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-[2-(thiophen-2-ylsulfanyl)-ethyl]-amine

2-(2-Bromo-ethylsulfanyl)-thiophene (51 mg, 0.22 mmol, 1.0 eq) is addedat room temperature to a stirred solution of1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (70mg, 0.22 mmol, 1.0 eq) in acetonitrile (5 mL). After 15 hours stirringat 90° C. the reaction mixture is concentrated to give a residue that ispurified by preparative HPLC to afford{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-[2-(thiophen-2-ylsulfanyl)-ethyl]-amineas a brown waxy solid (19 mg, 20% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.61 (s, 1H), 7.90 (d, J=9.1 Hz, 1H),7.66 (dd, J=1.2, 5.5 Hz, 1H), 7.34 (dd, J=2.8, 9.1 Hz, 1H), 7.25 (m,2H), 7.07 (dd, J=3.5, 5.3 Hz, 1H), 3.94 (s, 3H), 3.45 (t, J=6.8 Hz, 2H),2.92 (m, 6H), 2.68 (m, 3H), 2.07 (m, 2H), 1.80 (m, 2H), 1.32 (m, 2H).

MS m/z (+ESI): 461.2 [M+H]⁺.

Example 39 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as a yellow solid (61 mg, 56% yield)following Scheme 3 and in analogy to Example 35 using2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid (39 mg, 0.22 mmol 1.0eq) and1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (70mg, 0.22 mmol, 1.0 eq) as starting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.62 (s, 1H), 8.06 (d, J=7.8 Hz, 1H),7.90 (d, J=9.1 Hz, 1H), 7.28-7.39 (m, 4H), 6.90 (d, J=8.3 Hz, 1H), 4.28(m, 4H), 3.92 (s, 3H), 3.77 (m, 1H), 3.48 (t, J=7.0 Hz, 2H), 2.01 (m,2H), 2.70 (t, J=7.0 Hz, 2H), 2.12 (m, 2H), 1.78 (m, 2H), 1.57 (m, 2H).

MS m/z (+ESI): 481.2 [M+H]⁺.

Example 406-({1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amino)-methyl)-4H-benzo[1,4]oxazin-3-one

3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (354 mg, 2.00mmol, 1.0 eq) is added at room temperature to a stirred solution of1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine(0.65 g, 2.00 mmol, 1.0 eq) in 1,2-dichloroethane (4 mL) and methanol (1mL), followed by acetic acid (0.11 mL, 2.00 mmol, 1.0 eq) and sodiumcyanoborohydride (160 mg, 2.6 mmol, 1.4 eq). After 15 hours stirring atroom temperature, the reaction mixture is extracted with dichloromethane(3×20 mL) and a saturated sodium hydrogen carbonate aqueous solution (20mL). The combined organic layers are dried over sodium sulfate, filteredand concentrated to give a residue that is purified by preparative HPLCto afford6-({1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amino)-methyl)-4H-benzo[1,4]oxazin-3-oneas a white solid (500 mg, 52% yield).

¹H-NMR (400 MHz, DMSO-d6)

ppm: 10.60 (br, 1H), 8.58 (s, 1H), 7.86 (d, J=9.2 Hz, 1H), 7.30 (dd,J=2.8, 9.2 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 6.85 (m, 3H), 4.50 (s, 2H),3.91 (s, 3H), 3.60 (s, 2H), 3.42 (m, 2H), 2.87 (m, 2H), 2.62 (m, 2H),2.34 (s, 1H), 2.00 (m, 2H), 1.77 (m, 2H), 1.24 (m, 2H).

MS m/z (+ESI): 480.1 [M+H]⁺.

Example 41(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amine

The title compound is prepared as a light yellow oil (2.03 g, 78% yield)following Scheme 3 and in analogy to Example 40 using2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (792 mg, 4.77 mmol 1.0 eq)and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine(1.52 g, 4.77 mmol, 1.0 eq) as starting materials.

¹H-NMR (400 MHz, DMSO-d6)

ppm: 8.58 (s, 1H), 7.85 (d, J=9.2 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.24(s, 1H), 6.75 (m, 3H), 4.17 (s, 4H), 3.90 (s, 3H), 3.55 (s, 2H), 3.36(m, 2H), 2.85 (m, 2H), 2.55 (m, 2H), 2.31 (m, 1H), 1.97 (m, 2H), 1.74(m, 2H), 1.20 (m, 2H).

MS m/z (+ESI): 467.1 [M+H]⁺.

Example 42{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-(5-thiophen-2-yl-isoxazol-3-ylmethyl)-amine

The title compound is prepared as a yellow oil (57 mg, 52% yield)following Scheme 3 and in analogy to Example 40 using5-thiophen-2-yl-isoxazole-3-carbaldehyde (43 mg, 0.22 mmol 1.0 eq) and1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (70mg, 0.22 mmol, 1.0 eq) as starting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.61 (s, 1H), 7.89 (d, J=9.1 Hz, 1H),7.80 (dd, J=1.1, 5.0 Hz, 1H), 7.68 (dd, J=1.1, 3.6 Hz, 1H), 7.34 (dd,J=2.8, 9.1 Hz, 1H), 7.25 (m, 2H), 6.83 (s, 1H), 3.93 (s, 3H), 3.78 (s,2H), 3.46 (t, J=6.8 Hz, 2H), 2.92 (m, 2H), 2.78 (t, J=6.8 Hz, 2H), 2.41(m, 1H), 2.06 (m, 2H), 1.81 (m, 2H), 1.28 (m, 2H).

MS m/z (+ESI): 482.2 [M+H]⁺.

Example 43(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-methyl-amine

The title compound is prepared as a yellow foam (30 mg, 29% yield)following Scheme 3 and in analogy to Example 40 using paraformaldehyde(37 mg, 0.64 mmol 3.0 eq) and(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amine(100 mg, 0.22 mmol, 1.0 eq) as starting materials.

¹H-NMR (400 MHz, MeOH-d4)

ppm: 8.47 (s, 1H), 7.85 (d, J=9.2 Hz, 1H), 7.32 (m, 2H), 6.90 (m, 3H),4.62 (s, 3H), 4.25 (s, 4H), 3.97 (m, 5H), 3.53 (m, 2H), 2.85 (m, 2H),2.52 (s, 3H), 2.29 (m, 2H), 2.04 (m, 2H), 1.80 (m, 2H).

MS m/z (+ESI): 481.5 [M+H]⁺.

Example 44 7-chloro-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as an off-white solid (37 mg, 51% yield)following Scheme 3 and in analogy to Example 35 using7-chloro-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (29 mg,0.12 mmol 1.0 eq) and1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine asstarting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.62 (s, 1H), 8.17 (d, J=7.9 Hz, 1H),7.92 (d, J=9.1 Hz, 1H), 7.34 (dd, J=2.8, 9.1 Hz, 1H), 7.28 (d, J=2.8 Hz,1H), 6.94 (s, 1H), 6.51 (s, 1H), 6.38 (s, 1H), 3.94 (s, 3H), 3.69 (m,1H), 3.48 (m, 4H), 2.98 (m, 4H), 2.69 (t, J=7.0 Hz, 2H), 2.15 (m, 2H),1.77 (m, 2H), 1.49 (m, 2H).

MS m/z (+ESI): 530.2 [M+H]⁺.

Example 456-({1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one

The title compound is prepared as a yellow solid (48 mg, 44% yield)following Scheme 3 and in analogy to Example 40 using3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (40 mg,0.22 mmol 1.0 eq) and1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (70mg, 0.22 mmol, 1.0 eq) as starting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 11.20 (br, 1H), 8.61 (s, 1H), 7.90 (d,J=9.1 Hz, 1H), 7.32 (m, 3H), 7.02 (d, J=8.1 Hz, 1H), 4.61 (s, 2H), 3.94(s, 3H), 3.73 (s, 2H), 3.44 (t, J=7.0 Hz, 2H), 2.92 (m, 2H), 2.67 (t,J=7.0 Hz, 2H), 2.45 (m, 1H), 2.05 (m, 2H), 1.81 (m, 2H), 1.30 (m, 2H).

MS m/z (+ESI): 481.3 [M+H]⁺.

Example 466-({1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]thiazin-3-one

The title compound is prepared as a yellow waxy solid (54 mg, 48% yield)following Scheme 3 and in analogy to Example 40 using3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde (42 mg, 0.22 mmol1.0 eq) and1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (70mg, 0.22 mmol, 1.0 eq) as starting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.53 (s, 1H), 8.61 (s, 1H), 7.90 (d,J=9.1 Hz, 1H), 7.34 (dd, J=2.8, 9.1 Hz, 1H), 7.27 (d, J=2.8 Hz, 1H),7.24 (d, J=7.8 Hz, 1H), 6.96 (m, 2H), 3.94 (s, 3H), 3.68 (s, 2H), 3.45(m, 4H), 2.92 (m, 2H), 2.66 (t, J=7.0 Hz, 2H), 2.45 (m, 1H), 2.03 (m,2H), 1.82 (m, 2H), 1.29 (m, 2H).

MS m/z (+ESI): 496.2 [M+H]⁺.

Example 47(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-ethyl-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amine

The title compound is prepared as a yellow solid (67 mg, 20% yield)following Scheme 3 and in analogy to Example 40 using acetaldehyde (181μg, 3.21 mmol 5.0 eq) and(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amine(300 mg, 0.64 mmol, 1.0 eq) as starting materials.

¹H-NMR (400 MHz, MeOH-d4)

ppm: 8.46 (s, 1H), 7.83 (d, J=8.8 Hz, 1H), 6.75-6.84 (m, 3H), 7.30 (m,2H), 4.23 (s, 4H), 3.97 (s, 3H), 3.63 (s, 2H), 3.48 (m, 2H), 3.17 (m,2H), 2.68-2.78 (m, 5H), 2.15 (m, 2H), 1.84 (m, 2H), 1.65 (m, 2H), 1.05(m, 3H).

MS m/z (+ESI): 495.6 [M+H]⁺.

Example 487-chloro-6-({1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]thiazin-3-one

The title compound is prepared as a yellow solid (24 mg, 35% yield)following Scheme 3 and in analogy to Example 40 using7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde (30 mg,0.12 mmol 1.0 eq) and1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (40mg, 0.12 mmol, 1.0 eq) as starting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.63 (br, 1H), 8.61 (s, 1H), 7.90 (d,J=9.1 Hz, 1H), 7.38 (s, 1H), 7.34 (dd, J=2.8, 9.1 Hz, 1H), 7.27 (d,J=2.8 Hz, 1H), 7.21 (s, 1H), 3.94 (s, 3H), 3.71 (s, 2H), 3.45 (m, 4H),2.92 (m, 2H), 2.68 (m, 2H), 2.40 (m, 1H), 2.05 (m, 2H), 1.82 (m, 2H),1.29 (m, 2H).

MS m/z (+ESI): 530.2 [M+H]⁺.

Example 49(7-chloro-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amine

The title compound is prepared as a yellow waxy solid (23 mg, 34% yield)following

Scheme 3 and in analogy to Example 40 using7-chloro-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde (27 mg, 0.12mmol 1.0 eq) and1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (40mg, 0.12 mmol, 1.0 eq) as starting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.61 (s, 1H), 7.90 (d, J=9.1 Hz, 1H),7.34 (dd, J=2.8, 9.1 Hz, 1H), 7.28 (d, J=2.8 Hz, 1H), 6.86 (s, 1H), 6.68(s, 1H), 6.21 (br, 1H), 3.94 (s, 3H), 3.62 (s, 2H), 3.45 (m, 4H), 2.92(m, 4H), 2.68 (m, 2H), 2.42 (m, 1H), 2.08 (m, 2H), 1.82 (m, 2H), 1.29(m, 2H).

MS m/z (+ESI): 516 [M+H]⁺.

Example 50 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicacid{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as a yellow solid (7 mg, 10% yield)following Scheme 3 and in analogy to Example 35 using3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (26mg, 0.12 mmol, 1.0 eq) and1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (40mg, 0.12 mmol, 1.0 eq) as starting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 11.00 (s, 1H), 8.63 (s, 1H), 8.02 (d,J=8.0 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.91 (d, J=9.1 Hz, 1H), 7.59 (d,J=7.8 Hz, 1H), 7.35 (dd, J=2.8, 9.1 Hz, 1H), 7.28 (d, J=2.8 Hz, 1H),3.94 (s, 3H), 3.79 (m, 1H), 3.64 (s, 2H), 3.48 (t, J=7.0 Hz, 2H), 2.94(m, 2H), 2.72 (t, J=7.0 Hz, 2H), 2.28 (m, 2H), 1.78 (m, 2H), 1.52 (m,2H).

MS m/z (+ESI): 511.2 [M+H]⁺.

Example 517-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicacid{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as a yellow solid (9 mg, 12% yield)following Scheme 3 and in analogy to Example 35 using7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicacid (31 mg, 0.12 mmol, 1.0 eq) and1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (40mg, 0.12 mmol, 1.0 eq) as starting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 11.23 (s, 1H), 8.62 (s, 1H), 8.48 (d,J=7.8 Hz, 1H), 8.07 (s, 1H), 7.91 (d, J=9.1 Hz, 1H), 7.34 (dd, J=2.8,9.1 Hz, 1H), 7.28 (d, J=2.8 Hz, 1H), 3.95 (s, 3H), 3.75 (m, 1H), 3.61(s, 2H), 3.48 (t, J=7.0 Hz, 2H), 2.98 (m, 2H), 2.72 (t, J=7.0 Hz, 2H),2.22 (m, 2H), 1.82 (m, 2H), 1.50 (m, 2H).

MS m/z (+ESI): 545.2 [M+H]⁺.

Example 52 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-methyl-amidePreparation ofN-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-2-nitro-benzenesulfonamide

N,N-Diisopropylethylamine (318 μL, 1.82 mmol, 2.5 eq) is added at roomtemperature to a stirred solution of1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (237mg, 0.73 mmol, 1.0 eq) in dichloromethane (4 mL), followed by2-nitro-benzenesulfonyl chloride (183 mg, 0.80 mmol, 1.1 eq). After 2hours stirring at room temperature, the reaction mixture is extractedwith dichloromethane (3×10 mL) and water (10 mL). The combined organiclayers are dried over sodium sulfate, filtered and concentrated to givea residue that is purified by column chromatography (silica gel, eluent:ethyl acetate 100%) to affordN-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-2-nitro-benzenesulfonamideas a yellow waxy solid (307 mg, 82% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.59 (s, 1H), 8.18 (d, J=7.5 Hz, 1H),8.04 (m, 1H), 7.85-7.96 (m, 3H), 7.33 (dd, J=2.8, 9.1 Hz, 1H), 7.25 (d,J=2.6 Hz, 1H), 3.92 (s, 3H), 3.41 (t, J=7.0 Hz, 2H), 3.11 (m, 1H), 2.88(m, 2H), 2.62 (t, J=7.0 Hz, 2H), 2.02 (m, 2H), 1.60 (m, 2H), 1.45 (m,2H).

MS m/z (+ESI): 504.2 [M+H]⁺.

Preparation ofN-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-N-methyl-2-nitro-benzenesulfonamide

Cesium carbonate (293 mg, 0.90 mmol, 1.5 eq) is added at roomtemperature to a stirred solution ofN-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-2-nitro-benzenesulfonamide(307 mg, 0.60 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed bymethyl iodide (56 μL, 0.90 mmol, 1.5 eq). After 15 hours stirring atroom temperature, solvent is evaporated and the residue is extractedwith ethyl acetate (3×10 mL) and water (10 mL). The combined organiclayers are dried over sodium sulfate, filtered and concentrated to givea residue that is purified by column chromatography (silica gel, eluent:cyclohexane:ethyl acetate, 4:1 to 1:0, v/v) to affordN-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-N-methyl-2-nitro-benzenesulfonamideas a yellow solid (106 mg, 34% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.61 (s, 1H), 8.05 (m, 1H), 7.97 (m,1H), 7.85-7.90 (m, 3H), 7.34 (dd, J=2.8, 9.1 Hz, 1H), 7.26 (d, J=2.6 Hz,1H), 3.93 (s, 3H), 3.70 (m, 1H), 3.43 (t, J=6.9 Hz, 2H), 3.02 (m, 2H),2.78 (s, 3H), 2.67 (t, J=6.9 Hz, 2H), 2.10 (m, 2H), 1.68 (m, 2H), 1.40(m, 2H).

MS m/z (+ESI): 518.3 [M+H]⁺.

Preparation of{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-methyl-amine

1,8-diazabicyclo[5.4.0]undec-7-ene (36 μL, 0.24 mmol, 1.2 eq) is addedat room temperature to a stirred solution ofN-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-N-methyl-2-nitro-benzenesulfonamide(104 mg, 0.20 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL), followed by2-mercaptoethanol (56 μL, 0.90 mmol, 1.5 eq). After 15 hours stirring atroom temperature, solvent is evaporated and the residue is extractedwith ethyl acetate (3×10 mL) and water (10 mL). The combined organiclayers are dried over sodium sulfate, filtered and concentrated toafford{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-methyl-amineas a yellow oil (43 mg, 62% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.61 (s, 1H), 7.90 (d, J=9.1 Hz, 1H),7.34 (dd, J=2.7, 9.1 Hz, 1H), 7.27 (d, J=2.7 Hz, 1H), 3.94 (s, 3H), 3.45(t, J=7.0 Hz, 2H), 2.82 (m, 2H), 2.67 (t, J=7.0 Hz, 2H), 2.28 (m, 4H),2.07 (m, 2H), 1.78 (m, 2H), 1.20 (m, 2H).

MS m/z (+ESI): 333.3 [M+H]⁺.

Preparation of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-methyl-amide

3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (26 mg, 0.11mmol, 1.0 eq) is added at room temperature to a stirred solution of{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-methyl-amine(40 mg, 0.11 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL), followed byO-(7-azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluroniumhexafluorophosphate (45 mg, 0.11 mmol, 1.0 eq), and triethylamine (16μL, 0.11 mmol, 1.0 eq). After 4 hours stirring at room temperature,solvent is evaporated and the residue is purified by preparative HPLC toafford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-methyl-amideas a yellow solid (22 mg, 35% yield).

MS m/z (+ESI): 524.3 [M+H]⁺.

Example 53 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-yl}-amidePreparation of 2-(6-methoxy-quinolin-3-ylsulfanyl)-ethanol

2-Mercaptoethanol (0.11 mL, 1.51 mmol, 2.0 eq) is added at roomtemperature to a stirred solution of 3-bromo-6-methoxy-quinoline (200mg, 0.76 mmol, 1.0 eq) in N,N-dimethylformamide (10 mL), followed bysodium hydride (50%, 174 mg, 3.78 mol, 5.0 eq). After 4 hours stirringat 80° C., solvent is evaporated and the residue is extracted with ethylacetate (3×50 mL) and water (10 mL). The combined organic layers aredried over sodium sulfate, filtered and concentrated to give a crudeproduct that is purified by column chromatography (silica gel, eluent:ethyl acetate:hexane, 1:4 to 1:2, v/v) to afford2-(6-methoxy-quinolin-3-ylsulfanyl)-ethanol as a yellow viscous oil (140mg, 79% yield).

¹H-NMR (400 MHz, DMSO-d6)

ppm: 8.62 (s, 1H), 8.19 (d, J=12.0 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.30(m, 2H), 4.99 (t, J=6.0 Hz, 1H), 3.87 (s, 3H), 3.64 (t, J=6.0 Hz, 2H),3.16 (t, J=6.2 Hz, 2H).

MS m/z (+ESI): 236.1 [M+H]⁺.

Preparation of (6-methoxy-quinolin-3-ylsulfanyl)-acetaldehyde

Dess-Martin periodinane (400 mg, 0.94 mmol, 2.0 eq) is added at 0° C. toa stirred solution of 2-(6-methoxy-quinolin-3-ylsulfanyl)-ethanol (130mg, 0.55 mmol, 1.0 eq) in dichloromethane (5 mL). The reaction mixtureis stirred at room temperature for 1 hour, concentrated to give a crudeproduct that is directly engaged in the next step (130 mg, 100%).

MS m/z (+ESI): 234.0 [M+H]⁺.

Preparation of{1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester

Piperidin-4-yl-carbamic acid tert-butyl ester (3.4 g, 17.15 mmol, 1.0eq) is added at room temperature to a stirred solution of(6-methoxy-quinolin-3-ylsulfanyl)-acetaldehyde (4.0 g, 17.15 mmol, 1.0eq) in 1,2-dichloroethane (200 mL), followed by sodiumtriacetoxyborohydride (2.06 g, 34.3 mmol, 2.0 eq). After 1 hour stirringat room temperature, the reaction mixture is extracted withdichloromethane (3×50 mL) and a saturated sodium hydrogen carbonateaqueous solution (50 mL). The combined organic layers are dried oversodium sulfate, filtered and concentrated to give a crude product thatis purified by column chromatography (silica gel, eluent:dichloromethane:methanol, 20:1 to 10:1, v/v) to give a yellow solid thatis further recrystallized with ethyl acetate:hexane (1:6, v/v) to afford{1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester as a yellow oil (724 mg, 10% yield).

¹H-NMR (400 MHz, MeOH-d4)

ppm: 8.61 (d, J=2.0 Hz, 1H), 8.15 (s, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.29(m, 2H), 6.75 (d, J=7.6 Hz, 1H), 3.87 (s, 3H), 3.19 (m, 3H), 2.82 (m,2H), 2.56 (m, 2H), 1.96 (m, 2H), 1.65 (m, 2H), 1.35 (m, 11H).

MS m/z (+ESI): 418.4 [M+H]⁺.

Preparation of1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-ylamine

Trifluoroacetic acid (1.88 mL, 24.2 mmol, 15.0 eq) is added at 0° C. toa stirred solution of{1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester (724 mg, 1.61 mmol, 1.0 eq) in dichloromethane (75mL). After 15 hours stirring at room temperature, the reaction mixtureis extracted with dichloromethane (3×50 mL) and water (50 mL) and the pHvalue adjusted to 12 by the addition of a 1N sodium hydroxide aqueoussolution. The combined organic layers are dried over sodium sulfate,filtered and concentrated to afford1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-ylamine as abrown oil (544 mg, 99% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.64 (d, J=2.3 Hz, 1H), 8.18 (d, J=2.2Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.30-7.35 (m, 2H), 3.89 (s, 3H), 3.35(m, 1H), 3.22 (t, J=7.0 Hz, 2H), 2.82 (m, 2H), 2.64 (t, J=7.0 Hz, 2H),1.97 (m, 2H), 1.65 (m, 2H), 1.22 (m, 2H).

MS m/z (+ESI): 318.4 [M+H]⁺.

Preparation of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide

3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (21 mg, 0.09mmol, 1.0 eq) is added at room temperature to a stirred solution of1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-ylamine (30mg, 0.09 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL), followed by1-hydroxybenzotriazole (13 mg, 0.10 mmol, 1.1 eq),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (20 mg,0.10 mmol, 1.15 eq) and N,N-diisopropylethylamine (35 μL, 0.20 mmol,2.25 eq). After 15 hours stirring at room temperature, solvent isevaporated and the residue is extracted with dichloromethane (3×5 mL)and water (5 mL). The combined organic layers are dried over sodiumsulfate, filtered and concentrated to give a residue that is purified bypreparative HPLC to afford3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide asa white solid (30 mg, 59% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 11.65 (s, 1H), 8.65 (d, J=2.5 Hz, 1H),8.20-8.25 (m, 2H), 7.88 (d, J=8.8 Hz, 1H), 7.30-7.45 (m, 5H), 3.93 (s,3H), 3.75 (m, 1H), 3.50 (s, 2H), 3.29 (t, J=7.0 Hz, 2H), 2.95 (m, 2H),2.66 (t, J=7.0 Hz, 2H), 2.11 (m, 2H), 1.78 (m, 2H), 1.58 (m, 2H).

MS m/z (+ESI): 509.3 [M+H]⁺.

Example 54 7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid{1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as a white solid (13 mg, 24% yield)following Scheme 3 and in analogy to Example 53 using7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (22mg, 0.09 mmol, 1.0 eq) and1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-ylamine (30mg, 0.09 mmol, 1.0 eq) as starting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.73 (s, 1H), 8.65 (d, J=2.2 Hz, 1H),8.35 (d, J=7.7 Hz, 1H), 8.20 (d, J=2.2 Hz, 1H), 7.86 (m, 2H), 7.50 (s,1H), 7.30-7.37 (m, 3H), 3.93 (s, 3H), 3.70 (m, 1H), 3.52 (s, 2H), 3.25(t, J=7.0 Hz, 2H), 2.90 (m, 2H), 2.65 (t, J=7.0 Hz, 2H), 2.11 (m, 2H),1.78 (m, 2H), 1.50 (m, 2H).

MS m/z (+ESI): 543.3 [M+H]⁺.

Example 55 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicacid{1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as a light yellow solid (64 mg, 30%yield) following Scheme 3 and in analogy to Example 53 using3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (19mg, 0.09 mmol, 1.0 eq) and1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-ylamine (30mg, 0.09 mmol, 1.0 eq) as starting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 11.00 (s, 1H), 8.66 (d, J=2.2 Hz, 1H),8.20 (d, J=2.2 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H),7.88 (d, J=8.8 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.31-7.35 (m, 2H), 3.90(s, 3H), 3.78 (m, 1H), 3.64 (s, 2H), 3.26 (t, J=7.0 Hz, 2H), 2.86 (m,2H), 2.65 (t, J=7.0 Hz, 2H), 2.20 (m, 2H), 1.75 (m, 2H), 1.50 (m, 2H).

MS m/z (+ESI): 510.3 [M+H]⁺.

Example 567-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicacid{1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as a light yellow solid (49 mg, 91%yield) following Scheme 3 and in analogy to Example 53 using7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicacid (22 mg, 0.09 mmol, 1.0 eq) and1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-ylamine (30mg, 0.09 mmol, 1.0 eq) as starting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 11.22 (s, 1H), 8.65 (d, J=2.3 Hz, 1H),8.47 (d, J=7.8 Hz, 1H), 8.20 (d, J=2.2 Hz, 1H), 8.07 (s, 1H), 7.87 (d,J=9.0 Hz, 1H), 7.30-7.37 (m, 2H), 3.90 (s, 3H), 3.72 (m, 1H), 3.61 (s,2H), 3.26 (t, J=7.0 Hz, 2H), 2.90 (m, 2H), 2.65 (t, J=7.0 Hz, 2H), 2.15(m, 2H), 1.80 (m, 2H), 1.50 (m, 2H).

MS m/z (+ESI): 544.3 [M+H]⁺.

Example 57 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-hydroxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide

A solution of 1M boron tribromide in dichloromethane (2.93 mL, 2.93mmol, 8.0 eq) is added at 0° C. to a stirred solution of3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide (190mg, 0.37 mmol, 1.0 eq) in dichloromethane (2.5 mL). The reaction mixtureis stirred at 0° C. for 30 minutes and then at 40° C. for 24 hours. Thereaction mixture is cooled down to 0° C. before the addition of methanol(1 mL). Solvents are evaporated and the crude is taken in water (10 mL),the pH is adjusted to 10 by the addition of 1N sodium hydroxide aqueoussolution and the resulting aqueous layer is extracted withdichloromethane (3×10 mL). The combined organic layers are dried oversodium sulfate, filtered and concentrated to give a residue that ispurified by preparative HPLC to afford3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-hydroxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide as awhite lyophilizated powder (28 mg, 30% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.65 (s, 1H), 10.35 (br, 1H), 8.33 (s,1H), 8.23 (d, J=7.7 Hz, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.37-7.47 (m, 3H),7.15 (dd, J=2.5, 9.0 Hz, 1H), 7.04 (d, J=2.5 Hz, 1H), 4.53 (t, J=5.6 Hz,2H), 3.75 (m, 1H), 3.50 (s, 2H), 3.02 (m, 2H), 2.81 (t, J=5.6 Hz, 2H),2.18 (m, 2H), 1.78 (m, 2H), 1.55 (m, 2H).

MS m/z (+ESI): 480.3 [M+H]⁺.

Example 58 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-ethoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide

Ethyl bromide (12.8 μL, 0.17 mmol, 1.1 eq) is added at room temperatureto a stirred solution of3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-hydroxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide (75mg, 0.16 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), followed bypotassium carbonate (28.1 mg, 0.20 mmol, 1.3 eq). After 3 hours stirringat 60° C., solvent is evaporated and the residue is extracted withdichloromethane (3×5 mL) and water (5 mL). The combined organic layersare dried over sodium sulfate, filtered and concentrated to give aresidue that is purified by preparative HPLC to afford3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-ethoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide as awhite powder (15 mg, 18% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.64 (s, 1H), 8.40 (s, 1H), 8.19 (d,J=7.7 Hz, 1H), 7.87 (d, J=9.09 Hz, 1H), 7.36-7.48 (m, 3H), 7.23 (dd,J=2.7, 9.0 Hz, 1H), 7.19 (d, J=2.7 Hz, 1H), 4.55 (t, J=5.8 Hz, 2H), 4.20(q, J=6.9 Hz, 2H), 3.72 (m, 1H), 3.50 (s, 2H), 3.00 (m, 2H), 2.79 (t,J=5.8 Hz, 2H), 2.13 (m, 2H), 1.75 (m, 2H), 1.54 (m, 2H), 1.40 (t, J=6.9Hz, 3H).

MS m/z (+ESI): 508.2 [M+H]⁺.

Example 59 acetic acid3-(2-{4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidin-1-yl}-ethoxy)-quinoxalin-6-ylester

Acetyl chloride (11.4 μL, 0.16 mmol, 1.1 eq) is added at roomtemperature to a stirred solution of3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-hydroxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide (70mg, 0.15 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), followed bytriethylamine (40.7 μL, 0.29 mmol, 2.0 eq). After 1 hour stirring atroom temperature, solvent is evaporated and the residue is extractedwith dichloromethane (3×5 mL) and water (5 mL). The combined organiclayers are dried over sodium sulfate, filtered and concentrated to givea residue that is purified by preparative HPLC to afford acetic acid3-(2-{4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidin-1-yl}-ethoxy)-quinoxalin-6-ylester as a white powder (35 mg, 41% yield).

MS m/z (+ESI): 522.1 [M+H]⁺.

Example 60 methanesulfonic acid3-(2-{4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidin-1-yl}-ethoxy)-quinoxalin-6-ylester

Methanesulfonic anhydride (519 mg, 2.92 mmol, 20.0 eq) is added at 0° C.to a stirred solution of3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-hydroxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide (70mg, 0.15 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), followed bytriethylamine (610.4 μL, 4.38 mmol, 30.0 eq). After 30 minutes stirringat room temperature, solvent is evaporated and the residue is extractedwith dichloromethane (3×5 mL) and water (5 mL). The combined organiclayers are dried over sodium sulfate, filtered and concentrated to givea residue that is purified by preparative HPLC to afford methanesulfonicacid3-(2-{4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidin-1-yl}-ethoxy)-quinoxalin-6-ylester as an off-white powder (25 mg, 26% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.64 (s, 1H), 8.66 (s, 1H), 8.20 (d,J=7.7 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 7.80 (d, J=2.5 Hz, 1H), 7.60 (dd,J=2.5, 9.0 Hz, 1H), 7.40 (m, 3H), 4.58 (t, J=5.7 Hz, 2H), 3.75 (m, 1H),3.48 (s, 5H), 2.98 (m, 2H), 2.80 (t, J=5.7 Hz, 2H), 2.14 (m, 2H), 1.75(m, 2H), 1.54 (m, 2H).

MS m/z (+ESI): 558.1 [M+H]⁺.

Example 61[3-(2-{4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidin-1-yl}-ethoxy)-quinoxalin-6-yloxy]-aceticacid methyl ester

Bromo-acetic acid methyl ester (20.0 μL, 0.22 mmol, 1.05 eq) is added atroom temperature to a stirred solution of3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-hydroxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide (100mg, 0.21 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), followed bypotassium carbonate (57.6 mg, 0.42 mmol, 2.0 eq). After 5 hours stirringat room temperature, solvent is evaporated and the residue is extractedwith dichloromethane (3×5 mL) and water (5 mL). The combined organiclayers are dried over sodium sulfate, filtered and concentrated to givea residue that is purified by preparative HPLC to afford[3-(2-{4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidin-1-yl}-ethoxy)-quinoxalin-6-yloxy]-aceticacid methyl ester as a white powder (8 mg, 6% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.64 (s, 1H), 8.44 (s, 1H), 8.21 (d,J=7.7 Hz, 1H), 7.91 (d, J=9.0 Hz, 1H), 7.37-7.47 (m, 3H), 7.31 (dd,J=2.8, 9.0 Hz, 1H), 7.19 (d, J=2.8 Hz, 1H), 5.01 (s, 2H), 4.54 (t, J=5.7Hz, 2H), 3.72 (m, 1H), 3.70 (s, 3H), 3.49 (s, 2H), 2.99 (m, 2H), 2.78(t, J=5.7 Hz, 2H), 2.13 (m, 2H), 1.78 (m, 2H), 1.55 (m, 2H).

MS m/z (+ESI): 552.2 [M+H]⁺.

Example 62 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-difluoromethoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide

Chloro-difluoro-acetic acid ethyl ester (13.8 μL, 0.10 mmol, 1.0 eq) isadded at room temperature to a stirred solution of3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-hydroxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide (50mg, 0.10 mmol, 1.0 eq) in N,N-dimethylformamide (5 mL), followed bypotassium carbonate (14.4 mg, 0.10 mmol, 1.0 eq). After 15 hoursstirring at 70° C., solvent is evaporated and the residue is acidifiedwith 1N hydrochloric acid aqueous solution and the resulting aqueouslayer is extracted with ethyl acetate (3×10 mL). The combined organiclayers are dried over sodium sulfate, filtered and concentrated to givea residue that is purified by preparative HPLC to afford3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-difluoromethoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amideas a white lyophilizated powder (5 mg, 10% yield).

MS m/z (+ESI): 530.2 [M+H]⁺.

Example 63 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[3-methoxy-2-(7-methoxy-quinoxalin-2-yloxy)-propyl]-piperidin-4-yl}-amidePreparation of (1-oxiranylmethyl-piperidin-4-yl)-carbamic acidtert-butyl ester

Epibromohydrin (1.25 mL, 1.44 mmol, 1.0 eq) is added at room temperatureto a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester(3.0 g, 1.44 mmol, 1.0 eq) in N,N-dimethylformamide (90 mL), followed bypotassium carbonate (2.00 g, 1.43 mmol, 1.0 eq). After 24 hours stirringat room temperature, solvent is evaporated and the residue is extractedwith dichloromethane (3×40 mL) and water (40 mL). The combined organiclayers are dried over sodium sulfate, filtered and concentrated toafford (1-oxiranylmethyl-piperidin-4-yl)-carbamic acid tert-butyl esteras an off-white solid (3.86 g, 99% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 6.77 (d, J=7.9 Hz, 1H), 3.18 (m, 1H),2.98 (m, 1H), 2.80, 2.87 (2m, 2H), 2.68 (dd, J=4.3, 5.2 Hz, 1H), 2.58(dd, J=3.8, 13.3 Hz, 1H), 2.42 (dd, J=2.6, 5.2 Hz, 1H), 2.15 (dd, J=6.5,13.3 Hz, 1H), 1.96 (m, 2H), 1.65 (m, 2H), 1.39 (m, 11H).

MS m/z (+ESI): 257.4 [M+H]⁺.

Preparation of [1-(2-hydroxy-3-methoxy-propyl)-piperidin-4-yl]-carbamicacid tert-butyl ester

(1-Oxiranylmethyl-piperidin-4-yl)-carbamic acid tert-butyl ester (0.5 g,1.76 mmol, 1.0 eq) is dissolved at room temperature in a sodiummethylate solution in methanol (5.4M, 3 mL). After 48 hours stirring atroom temperature, the reaction mixture is cooled down to 0° C., quenchedby slow addition of water, concentrated. The residue is extracted withdichloromethane (3×5 mL) and water (5 mL). The combined organic layersare dried over sodium sulfate, filtered and concentrated to afford[1-(2-hydroxy-3-methoxy-propyl)-piperidin-4-yl]-carbamic acid tert-butylester as a yellow foam (0.49 g, 97% yield).

MS m/z (+ESI): 289.3 [M+H]⁺.

Preparation of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[3-methoxy-2-(7-methoxy-quinoxalin-2-yloxy)-propyl]-piperidin-4-yl}-amide

The title compound is prepared as an off-white lyophilizated powderfollowing Scheme 1 and in analogy to Example 1 using2-chloro-7-methoxy-quinoxaline,[1-(2-hydroxy-3-methoxy-propyl)-piperidin-4-yl]-carbamic acid tert-butylester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid asstarting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.62 (s, 1H), 8.39 (s, 1H), 8.14 (d,J=7.7 Hz, 1H), 7.88 (d, J=9.0 Hz, 1H), 7.33-7.42 (m, 3H), 7.25 (dd,J=3.0, 9.0 Hz, 1H), 7.18 (d, J=2.8 Hz, 1H), 5.69 (m, 1H), 3.91 (s, 3H),3.62-3.77 (m, 3H), 3.48 (s, 2H), 3.29 (s, 3H), 2.94, 3.08 (2m, 2H),2.53-2.73 (m, 2H), 2.09, 2.18 (2m, 2H), 1.70 (m, 2H), 1.37, 1.48 (2m,2H).

MS m/z (+ESI): 538.4 [M+H]⁺.

Example 64 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[3-(2-methoxy-ethoxy)-2-(7-methoxy-quinoxalin-2-yloxy)-propyl]-piperidin-4-yl}-amidePreparation of{1-[2-hydroxy-3-(2-methoxy-ethoxy)-propyl]-piperidin-4-yl}-carbamic acidtert-butyl ester

Sodium (57 mg, 2.56 mmol, 4.0 eq) is added at room temperature to astirred suspension of (1-oxiranylmethyl-piperidin-4-yl)-carbamic acidtert-butyl ester (200 mg, 0.64 mmol, 1.0 eq) in 2-methoxy-ethanol (4mL). After 72 hours stirring at room temperature, the reaction mixtureis cooled down to 0° C., cautiously quenched by the dropwise addition ofice-water, concentrated to afford{1-[2-hydroxy-3-(2-methoxy-ethoxy)-propyl]-piperidin-4-yl}-carbamic acidtert-butyl ester as an orange oil (210 mg, 99% yield).

MS m/z (+ESI): 333.4 [M+H]⁺.

Preparation of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[3-(2-methoxy-ethoxy)-2-(7-methoxy-quinoxalin-2-yloxy)-propyl]-piperidin-4-yl}-amide

The title compound is prepared as a white lyophilizated powder followingScheme 1 and in analogy to Example 1 using2-chloro-7-methoxy-quinoxaline,{1-[2-hydroxy-3-(2-methoxy-ethoxy)-propyl]-piperidin-4-yl}-carbamic acidtert-butyl ester and3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as startingmaterials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.62 (br, 1H), 8.39 (s, 1H), 8.14 (d,J=7.7 Hz, 1H), 7.88 (d, J=9.0 Hz, 1H), 7.33-7.42 (m, 3H), 7.26 (dd,J=2.7, 9.0 Hz, 1H), 7.18 (d, J=2.7 Hz, 1H), 5.67 (m, 1H), 3.91 (s, 3H),3.65-3.80 (m, 3H), 3.53-3.63 (m, 2H), 3.50 (s, 2H), 3.41 (m, 2H), 3.20(s, 3H), 2.63, 2.68 (2m, 2H), 2.58-2.72 (m, 2H), 2.09, 2.16 (2m, 2H),1.70 (m, 2H), 1.39, 1.50 (2m, 2H).

MS m/z (+ESI): 582.2 [M+H]⁺.

Example 65 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-3-morpholin-4-yl-propyl]-piperidin-4-yl}-amidePreparation of (1-thiiranylmethyl-piperidin-4-yl)-carbamic acidtert-butyl ester

Epithiochlorohydrine (268 mg, 2.40 mmol, 1.0 eq) is added at roomtemperature to a stirred solution of piperidin-4-yl-carbamic acidtert-butyl ester (500 mg, 2.40 mmol, 1.0 eq) in N,N-dimethylformamide(15 mL), followed by potassium carbonate (335 mg, 2.40 mmol, 1.0 eq).After 24 hours stirring at room temperature, solvent is evaporated andthe residue is extracted with dichloromethane (3×20 mL) and water (20mL). The combined organic layers are dried over sodium sulfate, filteredand concentrated to afford (1-thiiranylmethyl-piperidin-4-yl)-carbamicacid tert-butyl ester as a white solid (745 mg, 57% yield).

MS m/z (+ESI): 273.3 [M+H]⁺.

Preparation of[1-(2-mercapto-3-morpholin-4-yl-propyl)-piperidin-4-yl]-carbamic acidtert-butyl ester

Morpholine (80 μL, 0.83 mmol, 1.5 eq) is added at room temperature to astirred solution of (1-thiiranylmethyl-piperidin-4-yl)-carbamic acidtert-butyl ester (300 mg, 0.55 mmol, 1.0 eq) in ethanol (2 mL). Thereaction mixture is irradiated under microwave conditions for 4 minutesat 140° C. and 80 W and then solvent is evaporated to afford[1-(2-mercapto-3-morpholin-4-yl-propyl)-piperidin-4-yl]-carbamic acidtert-butyl ester as an off-white semisolid (266 mg, 67% yield).

MS m/z (+ESI): 360.3 [M+H]⁺.

Preparation of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-3-morpholin-4-yl-propyl]-piperidin-4-yl}-amide

The title compound is prepared as a light brown lyophilizated powderfollowing Scheme 3 and in analogy to Example 1 using2-chloro-7-methoxy-quinoxaline,[1-(2-mercapto-3-morpholin-4-yl-propyl)-piperidin-4-yl]-carbamic acidtert-butyl ester and3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as startingmaterials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.63 (s, 1H), 8.60 (s, 1H), 8.18 (d,J=7.8 Hz, 1H), 7.89 (d, J=9.1 Hz, 1H), 7.30-7.43 (m, 4H), 7.22 (d,J=2.7=Hz, 1H), 4.38 (m, 1H), 3.92 (s, 3H), 3.72 (m, 1H), 3.44-3.53 (m,10H), 3.05 (m, 2H), 2.60-2.78 (m, 4H), 2.15 (m, 2H), 1.72 (m, 2H), 1.52(m, 2H).

MS m/z (+ESI): 609.2 [M+H]⁺.

Example 66 (3S,4S)-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid{3-hydroxymethyl-1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amidePreparation of(3R,4S)-4-benzyloxycarbonylamino-1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidine-3-carboxylicacid ethyl ester

The title compound is prepared as a yellow oil following Scheme 1 and inanalogy to Example 1 using(3R,4S)-4-benzyloxycarbonylamino-piperidine-3-carboxylic acid ethylester (prepared according to procedures described in WO2005/066176),2-bromo-ethanol and 2-chloro-7-methoxy-quinoxaline as startingmaterials.

MS m/z (+ESI): 509.4 [M+H]⁺.

Preparation of(3R,4S)-4-amino-1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidine-3-carboxylicacid ethyl ester

10% Palladium on activated carbon (188 mg, 0.18 mmol, 0.5 eq) is addedat room temperature to a stirred solution of(3R,4S)-4-benzyloxycarbonylamino-1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidine-3-carboxylicacid ethyl ester (200 mg, 0.35 mmol, 1.0 eq) in methanol (20 mL). Themixture is hydrogenated for 4 hours, then filtered through decalite.Solvent is removed to afford(3R,4S)-4-amino-1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidine-3-carboxylicacid ethyl ester as a yellow oil (119 mg, 81% yield).

MS m/z (+ESI): 375.4 [M+H]⁺.

Preparation of(3R,4S)-1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidine-3-carboxylicacid ethyl ester

The title compound is prepared as a yellow oil (135 mg, 71% yield)following Scheme 1 and in analogy to Example 1 using(3R,4S)-4-amino1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidine-3-carboxylicacid ethyl ester and3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as startingmaterials.

MS m/z (+ESI): 566.4 [M+H]⁺.

Preparation of(3S,4S)-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{3-hydroxymethyl-1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide

Lithium aluminium hydride (1.0M solution in tetrahydrofuran, 80 μL, 0.08mmol, 1.0 eq) is added dropwise at −10° C. to a stirred solution of(3R,4S)-1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidine-3-carboxylicacid ethyl ester (50 mg, 0.08 mmol, 1.0 eq) in tetrahydrofuran (5 mL).After 30 minutes stirring at −10° C., the reaction mixture is cautiouslyquenched with ice-water (2 mL). Tetrahydrofuran is evaporated and thecrude is extracted with dichloromethane (3×10 mL) and water (10 mL). Thecombined organic layers are dried over sodium sulfate, filtered andconcentrated to give a residue that is purified by preparative HPLC toafford (3S,4S)-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{3-hydroxymethyl-1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amideas a yellow lyophilizated powder (6 mg, 14% yield).

MS m/z (+ESI): 524.3 [M+H]⁺.

Example 67 (3S,4R)-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid{3-hydroxymethyl-1-[1-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amidePreparation(3S,4R)-4-benzyloxycarbonylamino-1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidine-3-carboxylicacid ethyl ester

The title compound is prepared as an off-white solid (232 mg, 70% yield)following Scheme 3 and in analogy to Example 35 using(3S,4R)-4-benzyloxycarbonylamino-piperidine-3-carboxylic acid ethylester (200 mg, 0.63 mmol, 1.0 eq) (prepared according to proceduresdescribed in WO2005/066176) and(7-methoxy-quinoxalin-2-ylsulfanyl)-acetaldehyde (158 mg, 0.63 mmol 1.0eq) as starting materials.

MS m/z (+ESI): 525.4 [M+H]⁺.

Preparation(3S,4R)-4-amino-1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidine-3-carboxylicacid ethyl ester

Iodotrimethylsilane (26 μL, 0.18 mmol, 2.0 eq) is added at 0° C. to astirred solution of(3S,4R)-4-benzyloxycarbonylamino-1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidine-3-carboxylicacid ethyl ester (50 mg, 0.09 mmol, 1.0 eq) in dichloromethane (5 mL).After 2 hours stirring at 0° C. and 4 hours at room temperature, thereaction mixture is quenched with methanol (2 mL) and extracted withdichloromethane (3×5 mL) and a 0.1N hydrochloric acid aqueous solution(5 mL). The combined organic layers are dried over sodium sulfate,filtered and concentrated to afford(3S,4R)-4-amino-1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidine-3-carboxylicacid ethyl ester as a yellow oil (21 mg, 55% yield).

MS m/z (+ESI): 391.3 [M+H]⁺.

Preparation(3S,4R)-1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidine-3-carboxylicacid ethyl ester

The title compound is prepared as an orange semisolid (280 mg, 87%yield) following Scheme 3 and in analogy to Example 35 using(3S,4R)-4-amino-1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidine-3-carboxylicacid ethyl ester (216 mg, 0.50 mmol, 1.0 eq) and3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (113 mg, 0.50mmol, 1.0 eq) as starting material.

MS m/z (+ESI): 582.3 [M+H]⁺.

Preparation of(3R,4R)-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{3-hydroxymethyl-1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as a light yellow lyophilizated powder(38 mg, 32% yield) following Scheme 3 and in analogy to Example 66 using(3S,4R)-4-amino-1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidine-3-carboxylicacid ethyl ester (137 mg, 0.21 mmol, 1.0 eq) as starting material.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.67 (s, 1H), 8.62 (s, 1H), 8.21 (d,J=7.7 Hz, 1H), 7.91 (d, J=9.0 Hz, 1H), 7.29-7.41 (m, 5H), 4.62 (m, 1H),4.08 (m, 1H), 3.94 (s, 3H), 3.60 (m, 2H), 3.51 (s, 2H), 3.46 (m, 2H),2.79 (m, 2H), 2.70 (m, 2H), 2.33, 2.43 (2m, 2H), 1.99 (m, 1H), 1.67,1.76 (2m, 2H).

MS m/z (+ESI): 540.6 [M+H]⁺.

Example 68 7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid{1-[2-(7-methoxy-3-methyl-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amidePreparation of 4-methoxy-benzene-1,2-diamine

10% Palladium on activated carbon (1.0 g, 9.4 mmol, 0.15 eq) is added atroom temperature to a stirred solution of 4-methoxy-2-nitro-phenylamine(10.0 g, 59.5 mmol, 1.0 eq) in methanol (70 mL). The mixture ishydrogenated for 72 hours, then filtered through decalite. Solvent isremoved to afford 4-methoxy-benzene-1,2-diamine as a dark brown oil (8.0g, 97% yield).

¹H-NMR (400 MHz, MeOH-d4) δ ppm: 6.62 (d, J=8.4 Hz, 1H), 6.34 (d, J=2.8Hz, 1H), 6.18 (dd, J=2.8, 8.4 Hz, 1H), 3.82 (s, 3H).

Preparation of 7-methoxy-3-methyl-1H-quinoxalin-2-one

Pyruvic acid (60 mL, 868 mmol, 1.2 eq) is added at room temperature to astirred suspension of 4-methoxy-benzene-1,2-diamine (100 g, 724 mmol,1.0 eq) in 1.8M sulfuric acid aqueous solution (1000 mL). After 24 hoursstirring at room temperature, the reaction mixture is neutralized by theaddition of 1N sodium hydroxide aqueous solution. The resultingprecipitate is filtered and washed with water to afford7-methoxy-3-methyl-1H-quinoxalin-2-one as a dark purple solid (125 g,91% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 7.54 (d, J=8.8 Hz, 1H), 6.82 (dd, J,2.0, 8.8 Hz, 1H), 6.69 (d, J=2.0 Hz, 1H), 3.78 (s, 3H), 2.31 (s, 3H).

Preparation of 3-chloro-6-methoxy-2-methyl-quinoxaline

A solution of 7-methoxy-3-methyl-1H-quinoxalin-2-one (125 g, 631 mmol,1.0 eq) in phosphorus oxychloride (800 mL) is heated under reflux for 1hour. Then the reaction mixture is cooled down to room temperature andthe solvent is evaporated. The residue is poured into ice water and theresulting mixture is neutralized with 20% sodium hydroxide aqueoussolution. The resulting precipitate is collected by filtration, washedwith water to give a crude product that is purified by columnchromatography (silica gel, eluent: petroleum ether:ethyl acetate,100:1, v/v) to afford 3-chloro-6-methoxy-2-methyl-quinoxaline as a whitesolid (44.4 g, 34% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 7.86 (d, J=9.2 Hz, 1H), 7.42 (dd,J=2.4, 9.2 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 3.90 (s, 3H), 2.66 (s, 3H).

MS m/z (+ESI): 209.1 [M+H]⁺.

Preparation of7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-methoxy-3-methyl-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as a light yellow lyophilizated powderfollowing Scheme 1 and in analogy to Example 1 using3-chloro-6-methoxy-2-methyl-quinoxaline,[1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid asstarting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.70 (s, 1H), 8.35 (d, J=7.5 Hz, 1H),7.80 (d, J=8.8 Hz, 1H), 7.49 (s, 1H), 7.18-7.22 (m, 2H), 6.94 (s, 1H),4.55 (t, J=5.7 Hz, 2H), 3.90 (s, 3H), 3.71 (m, 1H), 3.51 (s, 2H), 2.98(m, 2H), 2.81 (t, J=5.7 Hz, 2H), 2.62 (s, 3H), 2.22 (m, 2H), 1.80 (m,2H), 1.50 (m, 2H).

MS m/z (+ESI): 542.3 [M+H]⁺.

Example 69 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-methylsulfanyl-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amidePreparation of 7-bromo-1H-quinoxalin-2-one

Bromine (7.36 mL, 147 mmol, 1.05 eq) is added at room temperature to astirred suspension of 1H-quinoxalin-2-one (20 g, 137 mmol, 1.0 eq) inacetic acid (400 mL). After 48 hours stirring at room temperature, thereaction mixture is poured into ice (500 mL) and the resultingprecipitate is collected by filtration, washed with water and ethylacetate to afford 7-bromo-1H-quinoxalin-2-one as a yellow solid (29.4 g,73% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 12.44 (br, 1H), 8.17 (s, 1H), 7.69 (d,J=8.8 Hz, 1H), 7.44 (m, 2H).

MS m/z (+ESI): 225.1 [M+H]⁺.

Preparation of 7-methylsulfanyl-1H-quinoxalin-2-one

A solution of 7-bromo-1H-quinoxalin-2-one (12.0 g, 53.3 mmol, 1.0 eq)and sodium methanethiolate (9.44 g, 133.3 mmol, 2.5 eq) inN-methylpyrrolidone is stirred at 160° C. for 1 hour. Then solvent isevaporated and the residue is dissolved in water, acidified to pH=5 with20% hydrochloric acid aqueous solution at 0° C., and the resultingprecipitate is collected by filtration, washed with water and ethylacetate to afford 7-methylsulfanyl-1H-quinoxalin-2-one as a yellow solid(9.23 g, 54% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 12.27 (br, 1H), 8.03 (s, 1H), 7.65 (d,J=8.4 Hz, 1H), 7.15 (dd, J=2.0, 8.4 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H),2.51 (s, 3H).

MS m/z (+ESI): 193.2 [M+H]⁺.

Preparation of 2-chloro-7-methylsulfanyl-quinoxaline

A solution of 7-methylsulfanyl-1H-quinoxalin-2-one (9.23 g, 48.0 mmol,1.0 eq) in phosphorus oxychloride (36 mL, 384.0 mmol, 8.0 eq) is heatedunder reflux for 30 minutes. Then the reaction mixture is cooled down toroom temperature and the solvent is evaporated. The residue is pouredinto ice water, the resulting mixture is basified with saturated sodiumhydrogen carbonate to pH=8˜9 and extracted with ethyl acetate (3×50 mL).The combined organic layers are dried over sodium sulfate, filtered andconcentrated to give a crude product that is purified by columnchromatography (silica gel, eluent: petroleum ether:dichloromethane, 4:1to 1:1, v/v) to afford 2-chloro-7-methylsulfanyl-quinoxaline as a greensolid (3.41 g, 33% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.86 (s, 1H), 7.99 (d, J=8.8 Hz, 1H),7.72-7.75 (m, 2H), 2.63 (s, 3H).

MS m/z (+ESI): 211.1 [M+H]⁺.

Preparation of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-methylsulfanyl-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as a light yellow lyophilizated powderfollowing Scheme 1 and in analogy to Example 1 using2-chloro-7-methylsulfanyl-quinoxaline,[1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as startingmaterials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.65 (s, 1H), 8.50 (s, 1H), 8.21 (d,J=7.7 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.37-7.53 (m, 5H), 4.56 (t, J=5.7Hz, 2H), 3.75 (m, 1H), 3.50 (s, 2H), 3.01 (m, 2H), 2.79 (t, J=5.7 Hz,2H), 2.62 (s, 3H), 2.15 (m, 2H), 1.77 (m, 2H), 1.55 (m, 2H).

MS m/z (+ESI): 510.3 [M+H]⁺.

Example 70 5-thiophen-2-yl-isoxazole-3-carboxylic acid{1-[2-(3-methoxy-quinolin-6-yloxy)-ethyl]-piperidin-4-yl}-amidePreparation of 3-methoxy-quinolin-6-ylamine

A suspension of 3-bromo-quinolin-6-ylamine (9.0 g, 40.3 mmol, 1.0 eq),sodium methoxide (10.9 g, 201.7 mmol, 5.0 eq) and copper powder (7.7 g,121.0 mmol, 3.0 eq) in methanol (240 mL) is heated at 135° C. for 15hours. The reaction mixture is then filtered and the filtrate isconcentrated to give a yellow residue that is purified by columnchromatography (silica gel, eluent: petroleum ether:ethylacetate:triethylamine, 2:1:0.05, v/v/v) to afford3-methoxy-quinolin-6-ylamine as a yellow solid (4.2 g, 59% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.16 (d, J=2.8 Hz, 1H), 7.58 (d, J=8.8Hz, 1H), 7.29 (d, J=2.8 Hz, 1H), 6.93 (dd, J=2.4, 8.8 Hz, 1H), 6.70 (d,J=2.4 Hz, 1H), 5.36 (s, 2H), 3.83 (s, 3H).

MS m/z (+ESI): 175.1 [M+H]⁺.

Preparation of 3-methoxy-quinolin-6-ol

A solution of sodium nitrite (3.49 g, 50.5 mmol, 1.1 eq) in water (20mL) is added dropwise at 0° C. to a stirred solution of3-methoxy-quinolin-6-ylamine (8.0 g, 45.9 mmol, 1.0 eq) in hydrochloricacid (160 mL, 321.3 mmol, 7.0 eq). The mixture is stirred at 0° C. for 2hours before its addition to a vigorously stirred solution of 10%sulfuric acid (600 mL) at 85-90° C. within 20 minutes. The resultingsolution is stirred at 90° C. for 1 hour, cooled down to roomtemperature, neutralized with sodium carbonate and extracted with ethylacetate (3×250 mL). The combined organic layers are dried over sodiumsulfate, filtered and concentrated to give a crude product that ispurified by column chromatography (silica gel, eluent: petroleumether:ethyl acetate:triethylamine, 3:1:0.1, v/v/v) to afford3-methoxy-quinolin-6-ol as a red solid (2.9 g, 34% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 9.91 (s, 1H), 8.35 (d, J=2.8 Hz, 1H),7.51 (d, J=2.8 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.07 (m, 2H), 3.86 (s,3H).

MS m/z (+ESI): 176.1 [M+H]⁺.

Preparation of 5-thiophen-2-yl-isoxazole-3-carboxylic acid{1-[2-(3-methoxy-quinolin-6-yloxy)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as a brown solid following Scheme 1 andin analogy to Example 2 using 3-methoxy-quinolin-6-ol,[1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and5-thiophen-2-yl-isoxazole-3-carboxylic acid as starting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.71 (d, J=8.0 Hz, 1H), 8.46 (d, J=2.8Hz, 1H), 7.78-7.87 (m, 3H), 7.63 (d, J=2.8 Hz, 1H), 7.32 (d, J=2.4 Hz,1H), 7.18-7.28 (m, 3H), 4.20 (t, J=5.8 Hz, 2H), 3.91 (s, 3H), 3.79 (m,1H), 3.00 (m, 2H), 2.79 (t, J=5.8 Hz, 2H), 2.18 (m, 2H), 1.78 (m, 2H),1.67 (m, 2H).

MS m/z (+ESI): 479.2 [M+H]⁺.

Example 71 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(2-methoxy-quinolin-7-yloxy)-ethyl]-piperidin-4-yl}-amidePreparation of 2-methoxy-quinolin-7-ol

2-Chloro-quinolin-7-ol (4.2 g, 23.4 mmol, 1.0 eq) is added at roomtemperature to a stirred solution of sodium methoxide in methanol (15%weight, 200 mL, 561.6 mmol, 24.0 eq) and the resulting mixture is heatedunder reflux for 20 hours. Solvent is removed, the residue is dissolvedin water (50 mL) and neutralized with acetic acid, followed byextraction with ethyl acetate (3×50 mL). The combined organic layers aredried over sodium sulfate, filtered and concentrated to give a crudeproduct that is purified by column chromatography (silica gel, eluent:petroleum ether:ethyl acetate, 6:1, v/v) to afford2-methoxy-quinolin-7-ol as a yellow solid (3.3 g, 79% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 9.99 (s, 1H), 8.03 (d, J=8.8 Hz, 1H),7.66 (d, J=8.4 Hz, 1H), 7.01 (d, J=3.0 Hz, 1H), 6.93 (dd, J=2.0, 8.4 Hz,1H), 6.72 (d, J=8.8 Hz, 1H), 3.91 (s, 3H).

MS m/z (+ESI): 176.1 [M+H]⁺.

Preparation of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(2-methoxy-quinolin-7-yloxy)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as a white lyophilizated powder followingScheme 1 and in analogy to Example 2 using 2-methoxy-quinolin-7-ol,[1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as startingmaterials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.64 (s, 1H), 8.23 (d, J=7.5 Hz, 1H),8.12 (m, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.30-7.45 (m, 3H), 7.20 (d, J=2.5Hz, 1H), 7.07 (dd, J=2.5, 8.8 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 4.23 (t,J=5.6 Hz, 2H), 3.96 (s, 3H), 3.75 (m, 1H), 3.49 (s, 2H), 3.00 (m, 2H),2.78 (t, J=5.6 Hz, 2H), 2.18 (m, 2H), 1.77 (m, 2H), 1.59 (m, 2H).

MS m/z (+ESI): 493.2 [M+H]⁺.

Example 72 7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid {1-[2-(7-cyano-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amidePreparation of 3-chloro-quinoxaline-6-carbonitrile

A solution of 3-oxo-3,4-dihydro-quinoxaline-6-carbonitrile (5.99 g, 35mmol, 1.0 eq) in phosphorus oxychloride (26 mL, 280 mmol, 8.0 eq) isheated under reflux for 1 hour. Then the reaction mixture is cooled downto room temperature and the solvent is evaporated. The residue is pouredinto ice water, the resulting mixture is neutralized with sodiumcarbonate and extracted with ethyl acetate (3×50 mL). The combinedorganic layers are dried over sodium sulfate, filtered and concentratedto give a crude product that is purified by column chromatography(silica gel, eluent: dichloromethane 100%) to afford3-chloro-quinoxaline-6-carbonitrile as a white solid (5.27 g, 79%yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 9.14 (s, 1H), 8.69 (d, J=1.6 Hz, 1H),8.29 (d, J=8.8 Hz, 1H), 8.19 (dd, J=1.6, 8.8 Hz, 1H).

MS m/z (+ESI): 190.2 [M+H]⁺.

Preparation of7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7-cyano-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as a yellow lyophilizated powderfollowing Scheme 1 and in analogy to Example 1 using3-chloro-quinoxaline-6-carbonitrile,[1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid asstarting materials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.61 (s, 1H), 8.77 (s, 1H), 8.39 (d,J=1.8 Hz, 1H), 8.32 (d, J=7.8 Hz, 1H), 8.17 (d, J=8.5 Hz, 1H), 7.97 (dd,J=1.8, 8.5 Hz, 1H), 7.48 (s, 1H), 6.92 (s, 1H), 4.57 (t, J=5.7 Hz, 2H),3.71 (m, 1H), 3.51 (s, 2H), 2.97 (m, 2H), 2.78 (t, J=5.7 Hz, 2H), 2.17(m, 2H), 1.78 (m, 2H), 1.45 (m, 2H).

MS m/z (+ESI): 523.2 [M+H]⁺.

Example 736-({1-[2-(7-fluoro-6-methoxy-quinolin-3-yloxy)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]thiazin-3-onePreparation of 7-fluoro-6-methoxy-quinolin-3-ol

A mixture of 7-fluoro-6-methoxy-quinolin-3-ylamine (prepared accordingto procedures described in FR2862301, 830 mg, 4.3 mmol, 1.0 eq) andconcentrated hydrochloric acid (12N, 3.0 g, 30.2 mmol, 7.0 eq) isstirred at 4° C. before the addition of sodium nitrite (313 mg, 4.7mmol, 1.1 eq) in water (24 mL). After 2 hours stirring at 4° C., theresulting mixture is added dropwise to a stirred solution ofconcentrated sulfuric acid (8.2 mL) and water (24 mL) at 90° C. within10 minutes. After 1 hour stirring at 90° C. the reaction mixture iscooled down to room temperature, neutralized with sodium hydrogencarbonate and extracted with ethyl acetate (3×80 mL). The combinedorganic layers are dried over sodium sulfate, filtered and concentratedto give a crude product that is recrystallized in methanol to afford7-fluoro-6-methoxy-quinolin-3-ol as an off-white solid (0.60 g, 72%yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.21 (s, 1H), 8.42 (d, J=2.7 Hz, 1H),7.64 (d, J=12.5 Hz, 1H), 7.48 (d, J=2.7 Hz, 1H), 7.40 (d, J=9.3 Hz, 1H),3.97 (s, 3H).

MS m/z (+ESI): 194.1 [M+H]⁺.

Preparation of6-({1-[2-(7-fluoro-6-methoxy-quinolin-3-yloxy)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]thiazin-3-one

The title compound is prepared as an off-white lyophilizated powderfollowing Scheme 1 and in analogy to Examples 2 and 9 using7-fluoro-6-methoxy-quinolin-3-ol,[1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde as startingmaterials.

MS m/z (+ESI): 497.2 [M+H]⁺.

Example 747-methoxy-2-(2-{trans-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-cyclohexyl}-ethoxy)-quinoline-3-carboxylicacid Preparation of7-methoxy-2-(2-{trans-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-cyclohexyl}-ethoxy)-quinoline-3-carboxylicacid methyl ester

The title compound is prepared as a light brown solid following Scheme 1and in analogy to Examples 1 and 28 using2-chloro-7-methoxy-quinoline-3-carboxylic acid,[trans-4-(2-hydroxy-ethyl)-cyclohexyl]-carbamic acid tert-butyl esterand 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid asstarting materials.

MS m/z (+ESI): 550.3 [M+H]⁺.

Preparation of7-methoxy-2-(2-{trans-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-cyclohexyl}-ethoxy)-quinoline-3-carboxylicacid

Lithium hydroxide monohydrate (18 mg, 0.42 mmol, 1.5 eq) is added atroom temperature to a stirred solution of7-methoxy-2-(2-{trans-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-cyclohexyl}-ethoxy)-quinoline-3-carboxylicacid methyl ester (173 mg, 0.28 mmol, 1.0 eq) in a mixture oftetrahydrofuran/water (6 mL, 2:1, v/v). After stirring at roomtemperature for 15 hours, solvents are evaporated and the residue isacidified to pH 5 with 0.5N hydrochloric acid aqueous solution and theresulting aqueous layer is extracted with dichloromethane (3×10 mL). Thecombined organic layers are dried over sodium sulfate, filtered andconcentrated to give a residue that is purified by preparative HPLC toafford7-methoxy-2-(2-{trans-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-cyclohexyl}-ethoxy)-quinoline-3-carboxylicacid as an off-white lyophilizated powder (11 mg, 6% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 12.85 (br, 1H), 10.63 (s, 1H), 8.62 (s,1H), 8.18 (d, J=7.9 Hz, 1H), 7.90 (d, J=8.9 Hz, 1H), 7.36-7.44 (m, 3H),7.16 (d, J=2.5 Hz, 1H), 7.10 (dd, J=2.5, 9.1 Hz, 1H), 4.50 (t, J=6.6 Hz,2H), 3.91 (s, 3H), 3.72 (m, 1H), 3.49 (s, 2H), 1.85 (m, 4H), 1.70 (m,2H), 1.48 (m, 1H), 1.32 (m, 2H), 1.11 (m, 2H).

MS m/z (+ESI): 536.3 [M+H]⁺.

Example 756-({1-[2-cyclopropyl-2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]thiazin-3-onePreparation of [1-(2-cyclopropyl-2-oxo-ethyl)-piperidin-4-yl]-carbamicacid tert-butyl ester

2-Bromo-1-cyclopropyl-ethanone (244 mg, 1.44 mmol, 1.0 eq) is added atroom temperature to a stirred solution of piperidin-4-yl-carbamic acidtert-butyl ester (300 mg, 1.44 mmol, 1.0 eq) in N,N-dimethylformamide(12 mL), followed by potassium carbonate (200 mg, 1.44 mmol, 1.0 eq).After 4 hours stirring at 60° C., solvent is evaporated and the residueis extracted with dichloromethane (3×30 mL) and water (30 mL). Thecombined organic layers are dried over sodium sulfate, filtered andconcentrated to afford[1-(2-cyclopropyl-2-oxo-ethyl)-piperidin-4-yl]-carbamic acid tert-butylester as a light yellow solid (425 mg, 99% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 6.76 (d, J=7.7 Hz, 1H), 4.96 (d, J=13.1Hz, 1H), 3.22 (s, 2H), 2.75 (m, 2H), 2.27 (m, 1H), 2.03 (m, 2H), 1.68(m, 2H), 1.42 (m, 2H), 1.38 (s, 9H), 0.87 (m, 2H), 0.80 (m, 2H).

MS m/z (+ESI): 283.3 [M+H]⁺.

Preparation of[1-(2-cyclopropyl-2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acidtert-butyl ester

Lithium aluminium hydride (1.0M solution in tetrahydrofuran, 1.41 mL,1.41 mmol, 1.0 eq) is added at 0° C. to a stirred solution of[1-(2-cyclopropyl-2-oxo-ethyl)-piperidin-4-yl]-carbamic acid tert-butylester (420 mg, 1.41 mmol, 1.0 eq) in tetrahydrofuran (25 mL). After 2hours stirring at 0° C., the reaction mixture is cautiously quenchedwith ice-water (5 mL). Tetrahydrofuran in evaporated and the crude isextracted with dichloromethane (3×30 mL) and water (30 mL). The combinedorganic layers are dried over sodium sulfate, filtered and concentratedto afford [1-(2-cyclopropyl-2-hydroxy-ethyl)-piperidin-4-yl]-carbamicacid tert-butyl ester as a white solid (373 mg, 84% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 6.73 (d, J=7.8 Hz, 1H), 4.12 (d, J=4.1Hz, 1H), 3.18 (m, 1H), 3.03 (m, 1H), 2.78 (m, 2H), 2.30 (m, 2H), 1.90,2.00 (2m, 2H), 1.62 (m, 2H), 1.39 (s, 9H), 1.36 (m, 2H), 0.77 (m, 1H),0.32 (m, 2H), 0.17, 0.22 (2m, 2H).

MS m/z (+ESI): 285.3 [M+H]⁺.

Preparation of6-({1-[2-cyclopropyl-2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]thiazin-3-one

The title compound is prepared as a white lyophilizated powder followingScheme 1 and in analogy to Examples 1 and 9 using2-chloro-7-methoxy-quinoxaline,[1-(2-cyclopropyl-2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acidtert-butyl ester and3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde as startingmaterials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.47 (s, 1H), 8.36 (s, 1H), 7.86 (d,J=9.0 Hz, 1H), 7.20 (m, 2H), 7.13 (d, J=2.8 Hz, 1H), 6.88 (m, 2H), 5.06(m, 1H), 3.90 (s, 3H), 3.59 (s, 2H), 3.40 (s, 2H), 2.99 (m, 1H), 2.78(m, 2H), 2.60 (m, 1H), 2.30 (m, 1H), 1.90, 2.07 (2m, 2H), 1.68 (m, 2H),1.14 (m, 2H), 0.98 (m, 1H), 0.57 (m, 1H), 1.47 (m, 2H), 1.38 (m, 1H).

MS m/z (+ESI): 520.2 [M+H]⁺.

Example 76 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7,8-dimethoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amidePreparation of 3,4-dimethoxy-2-nitro-benzoic acid

Potassium permanganate (0.6 g, 3.8 mmol, 2.0 eq), is added at roomtemperature to a stirred solution of 3,4-dimethoxy-2-nitro-benzaldehyde(0.4 g, 1.9 mmol, 1.0 eq) in acetic acid (10 mL). After stirringovernight at room temperature, the reaction mixture is quenched withsaturated sodium sulfite aqueous solution and extracted with ethylacetate (3×20 mL). The combined organic layers are dried over sodiumsulfate, filtered and concentrated to afford3,4-dimethoxy-2-nitro-benzoic acid as a white solid (0.35 g, 81% yield).

¹H-NMR (400 MHz, Acetone-d6) δ ppm: 7.86 (d, J=8.8 Hz, 1H), 7.34 (d,J=8.8 Hz, 1H), 4.06 (s, 3H), 3.89 (s, 3H).

MS m/z (−ESI): 226.1 [M−H]⁻.

Preparation of 3,4-dimethoxy-2-nitro-phenylamine

Thionyl chloride (10 mL, 137.4 mmol, 4.98 eq) is added at roomtemperature to a stirred solution of 3,4-dimethoxy-2-nitro-benzoic acid(6.26 g, 27.6 mmol, 1.0 eq) in 1,2-dichloroethane (100 mL). The reactionmixture is heated at 82° C. for 2 hours, then solvent is removed and theresulting crude acid chloride is dissolved in acetone (50 mL), cooleddown to 5° C. before the addition of a solution of sodium azide (10.0 g,154.0 mmol, 5.58 eq) in water (20 mL). After 1 hour stirring, thereaction mixture is poured into water (300 ml), the resulting whiteprecipitate of acyl azide is filtered, washed with water, dissolved inacetic acid (300 mL) and water (30 mL). The mixture is heated at 118° C.for 2 hours, then solvents are evaporated, the residue is taken in warmethanol and filtered. The filtrate is concentrated and the residue ispurified by column chromatography (silica gel, eluent: hexane:ethylacetate, 10:1 to 5:1, v/v) to afford 3,4-dimethoxy-2-nitro-phenylamineas a red solid (3.5 g, 64% yield).

¹H-NMR (400 MHz, Acetone-d6) δ ppm: 7.08 (d, J=8.8 Hz, 1H), 6.67 (d,J=8.8 Hz, 1H), 5.11 (br, 2H), 3.89 (s, 3H), 3.81 (s, 3H).

MS m/z (+ESI): 199.1 [M+H]⁺.

Preparation of (3,4-dimethoxy-2-nitro-phenylamino)-acetic acid

Bromoacetic acid (0.876 g, 6.31 mmol, 0.5 eq) is added portionwise to3,4-dimethoxy-2-nitro-phenylamine (2.5 g, 12.61 mmol, 1.0 eq) and themixture is stirred at 58° C. for 16 hours. The reaction is then quenchedby 25% ammonia in water and diluted with water. The solid is filteredoff and washed with 10% ammonia in water. The combined solutions areacidified by concentrated hydrochloric acid and the resultingprecipitate is collected by filtration, washed with water and driedunder vacuum to afford (3,4-dimethoxy-2-nitro-phenylamino)-acetic acidas a red solid (1.1 g, 34% yield).

¹H-NMR (400 MHz, MeOH-d4) δ ppm: 7.11 (d, J=9.2 Hz, 1H), 6.44 (d, J=9.2Hz, 1H), 3.91 (s, 2H), 3.89 (s, 3H), 3.81 (s, 3H).

MS m/z (+ESI): 257.3 [M+H]⁺.

Preparation of 7,8-dimethoxy-3,4-dihydro-1H-quinoxalin-2-one

10% Palladium on activated carbon (0.22 g, 2.06 mmol, 0.48 eq) is addedat room temperature to a stirred solution of(3,4-dimethoxy-2-nitro-phenylamino)-acetic acid (1.1 g, 4.29 mmol, 1.0eq) in methanol (30 mL). The mixture is hydrogenated for 16 hours, thenfiltered through decalite. Solvent is removed to afford7,8-dimethoxy-3,4-dihydro-1H-quinoxalin-2-one as an off-white solid(0.46 g, 52% yield).

¹H-NMR (400 MHz, Acetone-d6) δ ppm: 6.53 (d, J=8.8 Hz, 1H), 6.41 (d,J=8.8 Hz, 1H), 4.55 (br, 2H), 3.81 (s, 2H), 3.77 (s, 3H), 3.73 (s, 3H).

MS m/z (+ESI): 209.2 [M+H]⁺.

Preparation of 7,8-dimethoxy-quinoxalin-2-one

Sodium hydroxide (0.18 g, 4.42 mmol, 2.0 eq) is added at roomtemperature to a stirred solution of7,8-dimethoxy-3,4-dihydro-1H-quinoxalin-2-one (0.46 g, 2.21 mmol, 1.0eq) in water (5 mL), followed by 3% hydrogen peroxide (5 mL, 14.69 mmol,6.65 eq). The reaction mixture is heated under reflux for 3 hours, thenacidified with acetic acid to pH 5. The precipitate is collected byfiltration, dried under vacuum to afford 7,8-dimethoxy-quinoxalin-2-oneas a brown solid (0.3 g, 65% yield).

¹H-NMR (400 MHz, Acetone-d6) δ ppm: 7.92 (s, 1H), 7.50 (d, J=9.2 Hz,1H), 7.07 (d, J=9.2 Hz, 1H), 3.99 (s, 3H), 3.92 (s, 3H).

MS m/z (+ESI): 207.2 [M+H]⁺.

Preparation of 2-chloro-7,8-dimethoxy-quinoxaline

A solution of 7,8-dimethoxy-quinoxalin-2-one (5.0 g, 24.25 mmol, 1.0 eq)in phosphorus oxychloride (25 mL, 268.21 mmol, 11.06 eq) is heated underreflux for 1 hour. Then the reaction mixture is cooled down to roomtemperature and the solvent is evaporated. The residue is poured intoice water, the resulting mixture is neutralized with saturated sodiumhydrogen carbonate and extracted with ethyl acetate (3×50 mL). Thecombined organic layers are dried over sodium sulfate, filtered andconcentrated to give a crude product that is purified by columnchromatography (silica gel, eluent: hexane:ethyl acetate, 2:1 to 1:1,v/v) to afford 2-chloro-7,8-dimethoxy-quinoxaline as a light yellowsolid (4.2 g, 77% yield).

¹H-NMR (400 MHz, Acetone-d6) δ ppm: 8.70 (s, 1H), 7.86 (d, J=9.2 Hz,1H), 7.78 (d, J=9.2 Hz, 1H), 4.07 (s, 3H), 4.02 (s, 3H).

MS m/z (+ESI): 225.1 [M+H]⁺.

Preparation of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(7,8-dimethoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as a light brown solid following Scheme 3and in analogy to Example 35 using 2-chloro-7,8-dimethoxy-quinoxaline,2-mercaptoethanol, piperidin-4-yl-carbamic acid tort-butyl ester and3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as startingmaterials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.64 (br, 1H), 8.61 (s, 1H), 8.22 (d,J=7.8 Hz, 1H), 7.77 (d, J=9.3 Hz, 1H), 7.60 (d, J=9.3 Hz, 1H), 7.37-7.45(m, 3H), 3.98 (s, 3H), 3.97 (s, 3H), 3.73 (m, 1H), 3.57 (s, 2H), 3.48(m, 2H), 2.98 (m, 2H), 2.71 (m, 2H), 2.12 (m, 2H), 1.76 (m, 2H), 1.55(m, 2H).

MS m/z (+ESI): 540.2 [M+H]⁺.

Example 77 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(4-ethoxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-amidePreparation of 3-bromo-6-methoxy-[1,5]naphthyridin-4-ol

N-Bromosuccinimide (263 mg, 1.48 mmol, 1.3 eq) is added at 15° C. to astirred solution of 6-methoxy-[1,5]naphthyridin-4-ol (200 mg, 1.14 mmol,1.0 eq) in acetic acid (3 mL). After 30 minutes stirring at 15° C., thereaction mixture is allowed to come at room temperature and theresulting cake is filtered, washed with acetic acid and dried to afford3-bromo-6-methoxy-[1,5]naphthyridin-4-ol as an off-white solid (280 mg,97% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 12.90 (br, 1H), 8.45 (s, 1H), 7.97 (d,J=9.2 Hz, 1H), 7.20 (d, J=9.2 Hz, 1H), 3.93 (s, 3H).

MS m/z (+ESI): 255.0 [M+H]⁺.

Preparation of 8-benzyloxy-7-bromo-2-methoxy-[1,5]naphthyridine

Diethyl azodicarboxylate (1.37 g, 7.84 mmol, 2.0 eq) is added at roomtemperature to a stirred solution of3-bromo-6-methoxy-[1,5]naphthyridin-4-ol (1.0 g, 3.92 mmol, 1.0 eq),benzyl alcohol (640 mg, 5.88 mmol, 1.5 eq) and triphenylphosphine (2.05g, 7.84 mmol, 2.0 eq) in tetrahydrofuran (25 mL). After 15 hoursstirring at room temperature, tetrahydrofuran is evaporated and theresulting crude product is purified by column chromatography (silicagel, eluent: petroleum ether: ethyl acetate, 10:1, v/v) to afford8-benzyloxy-7-bromo-2-methoxy-[1,5]naphthyridine as a white solid (1.0g, 74% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.78 (s, 1H), 8.25 (d, J=9.6 Hz, 1H),7.45-7.60 (m, 2H), 7.24-7.40 (m, 4H), 5.84 (s, 2H), 4.03 (s, 3H).

MS m/z (+ESI): 345.0 [M+H]⁺.

Preparation of 4-benzyloxy-6-methoxy-[1,5]naphthyridin-3-ol

Tris(dibenzylideneacetone)dipalladium(0) (36 mg, 0.039 mmol, 0.02 eq) isadded at room temperature to a stirred solution of8-benzyloxy-7-bromo-2-methoxy-[1,5]naphthyridine (680 mg, 1.97 mmol, 1.0eq) in water (10 mL), and dioxane (20 mL), followed by4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (47 mg, 0.099 mmol, 0.05eq) and a solution of potassium hydroxide (220 mg, 3.94 mmol, 2.0 eq) inwater (10 mL). After 6 hours stirring at 90° C., the reaction mixture isquenched with a 1N hydrochloric acid aqueous solution (4 mL) andextracted with ethyl acetate (3×10 mL). The combined organic layers aredried over sodium sulfate, filtered and concentrated to give a residuethat is purified by column chromatography (silica gel, eluent: petroleumether:ethyl acetate, 4:1, v/v) to afford4-benzyloxy-6-methoxy-[1,5]naphthyridin-3-ol as a light yellow solid(278 mg, 53% yield).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 8.59 (s, 1H), 8.21 (d, J=8.8 Hz, 1H),7.25-7.43 (m, 5H), 7.01 (d, J=8.8 Hz, 1H), 5.86 (s, 2H), 4.08 (s, 3H).

MS m/z (+ESI): 283.1 [M+H]⁺.

Preparation of{1-[2-(4-benzyloxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester

Diethyl azodicarboxylate (5.48 g, 31.46 mmol, 2.0 eq) is added at roomtemperature to a stirred solution of4-benzyloxy-6-methoxy-[1,5]naphthyridin-3-ol (4.44 g, 15.73 mmol, 1.0eq), [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester(5.76 g, 23.59 mmol, 1.5 eq) and triphenylphosphine (8.25 g, 31.46 mmol,2.0 eq) in tetrahydrofuran (150 mL). After 15 hours stirring at roomtemperature, tetrahydrofuran is evaporated and the resulting crudeproduct is purified by column chromatography (silica gel, eluent: ethylacetate:methanol, 10:0 to 9:1, v/v) to afford{1-[2-(4-benzyloxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester as a light brown viscous oil (9.31 g, 88% yield).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 8.51 (s, 1H), 8.05 (d, J=8.8 Hz, 1H),7.47 (m, 2H), 7.28 (m, 3H), 6.93 (d, J=8.8 Hz, 2H), 5.59 (s, 2H), 4.60(s, 1H), 4.23 (t, J=5.6 Hz, 2H), 4.01 (s, 3H), 3.38 (m, 1H), 2.85 (m,2H), 2.73 (m, 2H), 2.15 (m, 2H), 1.85 (m, 2H), 1.38, (m, 11H).

MS m/z (+ESI): 509.2 [M+H]⁺.

Preparation of{1-[2-(4-hydroxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester

10% Palladium on activated carbon (3.45 g, 3.29 mmol, 0.18 eq) is addedat room temperature to a stirred solution of{1-[2-(4-benzyloxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester (9.3 g, 18.28 mmol, 1.0 eq) in methanol (100 mL).The mixture is hydrogenated for 7 hours, then filtered through decalite.Solvent is removed to afford{1-[2-(4-hydroxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester as an off-white solid (7.1 g, 91% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.20 (s, 1H), 8.11 (d, J=9.0 Hz, 1H),7.17 (d, J=9.0 Hz, 1H), 7.07 (d, J=6.7 Hz, 1H), 4.28 (t, J=4.9 Hz, 2H),3.97 (s, 3H), 3.51 (m, 1H), 3.40 (m, 2H), 3.22 (m, 2H), 2.98 (m, 2H),1.95 (m, 2H), 1.74 (m, 2H), 1.39 (s, 9H).

MS m/z (+ESI): 419.4 [M+H]⁺.

Preparation of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(4-hydroxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-amide

The title compound is prepared as a white lyophilizated powder followingScheme 1 and in analogy to Example 1 using{1-[2-(4-hydroxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester and3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as startingmaterials.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.65 (s, 1H), 8.32 (d, J=7.2 Hz, 1H),8.01 (d, J=9.0 Hz, 1H), 7.38-7.49 (m, 4H), 7.10 (d, J=9.0 Hz, 1H), 4.18(m, 2H), 3.98 (s, 3H), 3.79 (m, 1H), 3.50 (s, 2H), 3.05 (m, 2H), 2.70(t, J=5.6 Hz, 2H), 2.22 (m, 2H), 1.81 (m, 2H), 1.67 (m, 2H).

MS m/z (+ESI): 510.6 [M+H]⁺.

Preparation of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(4-ethoxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-amide

Ethyl iodide (13 μL, 0.16 mmol, 1.0 eq) is added at room temperature toa stirred solution of3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(4-hydroxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-amide(90 mg, 0.16 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed bypotassium carbonate (22 mg, 0.16 mmol, 1.0 eq). After 3 hours stirringat room temperature, solvent is evaporated and the residue is extractedwith dichloromethane (3×10 mL) and water (10 mL). The combined organiclayers are dried over sodium sulfate, filtered and concentrated to givea residue that is purified by preparative HPLC to afford3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid{1-[2-(4-ethoxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-amideas a white lyophilizated powder (29 mg, 32% yield).

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 10.65 (s, 1H), 8.70 (s, 1H), 8.24 (d,J=7.6 Hz, 1H), 8.18 (d, J=9.0 Hz, 1H), 7.37-7.48 (m, 3H), 7.11 (d, J=9.0Hz, 1H), 4.56 (q, J=7.0 Hz, 2H), 4.35 (t, J=5.5 Hz, 2H), 4.01 (s, 3H),3.72 (m, 1H), 3.50 (s, 2H), 2.99 (m, 2H), 2.76 (t, J=5.5 Hz, 2H), 2.17(m, 2H), 1.77 (m, 2H), 1.58 (m, 2H), 1.39 (t, J=7.0 Hz, 3H).

MS m/z (+ESI): 538.6 [M+H]⁺.

The examples listed in the following table are prepared using procedurespreviously described:

Expl./ Reference Reference for 1H-NMR MS m/z Comp. Scheme Preparation(400 MHz, DMSO-d6) δ ppm (+ESI) 78 1 Example 1  — 510.3 WO2005066176[M + H]⁺ 79 1 Example 1  — 510.4 WO2004058144 [M + H]⁺ 80 1 Example 1 10.64 (s, 1H), 8.39 (s, 1H), 7.87 (d, J = 8.8 Hz, 510.3 WO20040581441H), 7.74 (d, J = 7.2 Hz, 1H), 7.44 (m, 2H), [M + H]⁺ 7.37 (d, J = 8.0Hz, 1H), 7.21-7.25 (m, 2H), 4.53-4.57 (m, 2H), 3.90 (s, 3H), 3.84 (m,1H), 3.76 (m, 1H), 3.48 (s, 2H), 2.90 (m, 1H), 2.87 (m, 1H), 2.80 (m,2H), 2.38 (m, 1H), 2.25 (m, 1H), 1.53, 1.90 (2m, 2H) 81 1 Example 1 10.64 (br, 1H), 8.40 (s, 1H), 8.13 (m, 1H), 7.87 510.4 WO2005066176 (d,J = 8.8 Hz, 1H), 7.45 (m, 2H), 7.37 (d, J = [M + H]⁺ 8.0 Hz, 1H), 7.23(m, 2H), 4.55 (m, 2H), 3.90 (s, 3H), 3.57 (m, 1H), 3.52 (m, 1H), 3.48(s, 2H), 3.09 (m, 1H), 2.90 (m, 1H), 2.80 (m, 2H), 2.07 (m, 1H), 1.93(m, 1H), 1.44, 1.77 (2m, 2H) 82 1 Example 58 — 538.2 [M + H]⁺ 83 1Example 58 — 575.1 [M + H]⁺ 84 1 Example 58 10.64 (s, 1H), 8.61 (s, 1H),8.21 (d, J = 7.7 Hz, 552.1 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.64 (d, J =2.5 [M + H]⁺ Hz, 1H), 7.35-7.50 (m, 4H), 4.58 (t, J = 5.7 Hz, 2H), 4.40(s, 2H), 3.72 (m, 1H), 3.50 (s, 2H), 3.42 (s, 3H), 2.99 (m, 2H), 2.78(m, 2H), 2.15 (m, 2H), 1.75 (m, 2H), 1.55 (m, 2H) 85 1 Example 58 —664.1 [M + H]⁺ 86 1 Example 58 — 594.2 [M + H]⁺ 87 1 Example 58 — 550.2[M + H]⁺ 88 1 Example 58 — 522.2 [M + H]⁺ 89 1 Example 58 10.65 (s, 1H),8.43 (s, 1H), 8.21 (d, J = 7.8 Hz, 600.2 1H), 7.90 (d, J = 9.8 Hz, 1H),7.28-7.47 (m, [M + H]⁺ 7H), 6.92-7.02 (m, 3H), 4.57 (t, J = 5.7 Hz, 2H),4.50 (m, 2H), 4.38 (m, 2H), 3.74 (m, 1H), 3.49 (s, 2H), 2.99 (m, 2H),2.78 (t, J = 5.7 Hz, 2H), 2.14 (m, 2H), 1.76 (m, 2H), 1.53 (m, 2H) 90 1Example 58 10.64 (s, 1H), 8.41 (s, 1H), 8.21 (d, J = 7.7 Hz, 594.2 1H),7.88 (d, J = 9.0 Hz, 1H), 7.37-7.43 (m, [M + H]⁺ 3H), 7.24 (dd, J = 2.7,9.0 Hz, 1H), 7.18 (d, J = 2.7 Hz, 1H), 4.76 (t, J = 5.3 Hz, 1H), 4.55(t, J = 5.7 Hz, 2H), 4.19 (t, J = 6.5 Hz, 2H), 4.02 (m, 2H), 3.72 (m,3H), 3.49 (s, 2H), 2.99 (m, 2H), 2.78 (t, J = 5.7 Hz, 2H), 2.14 (m, 2H),2.00 (m, 2H), 1.89 (m, 1H), 1.76 (m, 2H), 1.53 (m, 2H), 1.34 (m, 1H) 911 Example 58 10.64 (s, 1H), 8.40 (s, 1H), 8.21 (d, J = 7.7 Hz, 538.21H), 7.88 (d, J = 9.0 Hz, 1H), 7.36-7.45 (m, [M + H]⁺ 3H), 7.24 (dd, J =2.7, 9.0 Hz, 1H), 7.20 (d, J = 2.5 Hz, 1H), 4.55 (m, 3H), 4.20 (t, J =6.4 Hz, 2H), 3.75 (m, 1H), 3.60 (m, 2H), 3.50 (s, 2H), 3.00 (m, 2H),2.79 (t, J = 5.7 Hz, 2H), 2.13 (m, 2H), 1.92 (m, 2H), 1.78 (m, 2H), 1.55(m, 2H) 92 1 Example 58 10.64 (s, 1H), 8.42 (s, 1H), 8.21 (d, J = 7.7Hz, 547.2 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.36-7.45 (m, [M + H]⁺ 3H),7.24 (m, 2H), 4.55 (t, J = 6.0 Hz, 2H), 4.22 (t, J = 6.0 Hz, 2H), 3.75(m, 1H), 3.50 (s, 2H), 2.98 (m, 2H), 2.78 (t, J = 6.0 Hz, 2H), 2.69 (t,J = 7.1 Hz, 2H), 2.12 (m, 4H), 1.75 (m, 2H), 1.53 (m, 2H) 93 1 Example58 10.65 (s, 1H), 8.40 (s, 1H), 8.21 (d, J = 7.5 Hz, 522.2 1H), 7.88 (d,J = 9.0 Hz, 1H), 7.36-7.46 (m, [M + H]⁺ 3H), 7.25 (dd, J = 2.7, 9.0 Hz,1H), 7.19 (d, J = 2.5 Hz, 1H), 4.55 (t, J = 5.7 Hz, 2H), 4.10 (t, J =6.5 Hz, 2H), 3.74 (m, 1H), 3.49 (s, 2H), 3.00 (m, 2H), 2.78 (t, J = 5.7Hz, 2H), 2.13 (m, 2H), 1.78 (m, 4H), 1.55 (m, 2H), 1.02 (t, J = 7.4 Hz,3H) 94 1 Example 1  10.63 (s, 1H), 8.35 (s, 1H), 8.15 (d, J = 7.7 Hz,508.1 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.34-7.43 (m, [M + H]⁺ 3H), 7.23(dd, J = 3.0, 9.0 Hz, 1H), 7.19 (d, J = 530.1 2.8 Hz, 1H), 5.58 (m, 1H),3.91 (s, 3H), 3.71 [M + Na]⁺ (m, 1H), 3.48 (s, 2H), 2.88, 3.08 (2m, 2H),2.58, 2.70 (2m, 2H), 2.11 (m, 2H), 1.70 (m, 2H), 1.48 (m, 2H), 1.37 (d,J = 6.2 Hz, 3H) 95 1 Example 1  10.63 (s, 1H), 8.44 (s, 1H), 8.17 (d, J= 7.8 Hz, 526.1 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.34-7.42 (m, [M + H]⁺3H), 7.27 (dd, J = 2.8, 9.0 Hz, 1H), 7.19 (d, J = 2.8 Hz, 1H), 5.71,5.78 (2m, 1H), 4.71, 4.82 (2m, 2H), 3.91 (s, 3H), 3.70 (m, 1H), 3.50 (s,2H), 3.03 (m, 2H), 2.70 (m, 2H), 2.18 (m, 2H), 1.73 (m, 2H), 1.47 (m,2H) 96 1 Example 1  10.49 (s, 1H), 8.41 (s, 1H), 7.88 (d, J = 9.0 Hz,506.2 Example 9  1H), 7.23 (m, 3H), 6.92 (m, 2H), 5.98 (m, 1H), [M + H]⁺5.20-5.40 (m, 2H), 3.92 (s, 3H), 3.70 (m, 1H), 3.65 (s, 2H), 3.41 (s,2H), 2.86, 2.96 (2m, 2H), 2.60, 2.72 (2m, 2H), 2.35 (m, 1H), 2.05, 2.10(2m, 2H), 1.72 (m, 2H), 1.11, 1.21 (2m, 2H) 97 1 Example 1  10.63 (s,1H), 8.38 (s, 1H), 8.14 (d, J = 7.8 Hz, 522.2 1H), 7.87 (d, J = 9.0 Hz,1H), 7.33-7.42 (m, [M + H]⁺ 3H), 7.23 (dd, J = 2.7, 9.0 Hz, 1H), 7.17(d, J = 2.7 Hz, 1H), 5.51 (m, 1H), 3.91 (s, 3H), 3.70 (m, 1H), 3.49 (s,2H), 2.92, 3.12 (2m, 2H), 2.58, 2.70 (2m, 2H), 2.09, 2.19 (2m, 2H), 1.82(m, 1H), 1.70 (m, 3H), 1.34, 1.48 (2m, 2H), 0.95 (t, J = 7.5 Hz, 3H) 981 Example 1  10.45 (s, 1H), 8.34 (s, 1H), 7.86 (d, J = 9.0 Hz, 570.3Example 9  1H), 7.15-7.38 (m, 7H), 7.04 (d, J = 2.8 Hz, [M + H]⁺WO2008093737 1H), 6.89 (s, 1H), 6.82 (d, J = 8.0 Hz, 1H), 4.68 (m, 1H),4.50 (m, 1H), 4.19 (d, J = 13.5 Hz, 1H), 3.79 (s, 3H), 3.48-3.62 (m,2H), 3.41 (s, 2H), 3.22 (m, 2H), 2.77 (m, 1H), 2.40 (m, 2H), 2.12 (m,2H), 1.95 (m, 1H), 1.67-1.82 (m, 2H), 1.08, 1.47 (2m, 2H) 99 1 Example66 — 524.3 WO2005066176 [M + H]⁺ 100 2 Example 28 10.64 (s, 1H), 9.99(br, 1H), 8.48 (d, J = 8.6 492.1 Hz, 1H), 8.10 (dd, J = 2.1, 8.6 Hz,1H), 7.37- [M + H]⁺ 7.59 (m, 5H), 7.20 (dd, J = 1.5, 7.5 Hz, 1H), 514.15.75 (s, 1H), 4.24 (d, J = 6.5 Hz, 2H), 3.76 (m, [M + Na]⁺ 1H), 3.47 (s,2H), 1.90 (m, 4H), 1.80 (m, 1H), 1.40 (m, 2H), 1.25 (m, 2H) 101 2Example 28 — 540.1 [M + H]⁺ 102 3 Example 35 11.08 (br, 1H), 8.69 (d, J= 2.1 Hz, 1H), 8.20 531.2 Example 40 (m, 1H), 8.03 (d, J = 2.0 Hz, 1H),7.94 (s, 1H), [M + H]⁺ 7.18 (d, J = 9.0 Hz, 1H), 4.00 (s, 3H), 3.81 (s,2H), 3.57 (s, 2H), 3.30 (m, 2H), 2.86 (m, 2H), 2.62 (t, J = 6.9 Hz, 2H),2.42 (m, 1H), 2.01 (m, 2H), 1.80 (m, 2H), 1.30 (m, 2H) 103 3 Example 3511.36 (br, 1H), 8.71 (d, J = 2.2, 1H), 8.23 (d, 495.3 J = 9.0 Hz, 1H),8.05 (d, J = 2.1 Hz, 1H), 7.83 [M + H]⁺ (d, J = 8.3 Hz, 1H), 7.60 (d, J= 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 9.0 Hz, 1H), 4.74(s, 2H), 4.01 (s, 3H), 3.75 (m, 1H), 3.30 (m, 2H), 2.88 (m, 2H), 2.67(t, J = 6.8 Hz, 2H), 2.19 (m, 2H), 1.84 (m, 2H), 1.54 (m, 2H) 104 3Example 35 10.66 (s, 1H), 8.59 (s, 1H), 8.42 (t, J = 5.7 Hz, 524.1 1H),7.78 (d, J = 9.1 Hz, 1H), 7.40-7.55 (m, [M + H]⁺ 4H), 7.26 (d, J = 2.8Hz, 1H), 3.92 (s, 3H), 3.48 (s, 2H), 3.42 (m, 2H), 3.13 (m, 2H), 2.84(m, 2H), 2.65 (m, 2H), 2.02 (m, 1H), 1.81 (m, 2H), 1.62 (m, 2H), 1.41(m, 1H), 0.94 (m, 1H) 105 3 Example 9  10.50 (s, 1H), 8.59 (s, 1H), 7.88(d, J = 9.0 Hz, 526.5 Example 67 1H), 7.18-7.35 (m, 3H), 6.94 (m, 2H),3.93 (s, [M + H]⁺ WO2005066176 3H), 3.37-3.65 (m, 9H), 2.60-2.77 (m,4H), 2.25 (m, 2H), 1.88 (m, 1 H), 1.52 (m, 2H) 106 1 Example 1  10.62(s, 1H), 8.39 (s, 1H), 8.14 (d, J = 7.8 Hz, 552.2 Example 63 1H), 7.88(d, J = 9.0 Hz, 1H), 7.33-7.42 (m, [M + H]⁺ 3H), 7.25 (dd, J = 2.7, 9.0Hz, 1H), 7.18 (d, J = 2.7 Hz, 1H), 5.67 (m, 1H), 3.91 (s, 3H), 3.68 (m,3H), 3.42-3.55 (m, 4H), 2.92, 3.07 (2 m, 2H), 2.58-2.72 (m, 2H), 2.09,2.18 (2 m, 2H), 1.70 (m, 2H), 1.37, 1.48 (2 m, 2H), 1.08 (t, J = 7.0 Hz,3H) 107 1 Example 1  10.63 (br, 1H), 8.40 (s, 1H), 8.14 (d, J = 7.8614.7 Example 64 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.18-7.42 [M + H]⁺(m, 10H), 5.73 (m, 1H), 4.54 (q, J = 12.2 Hz, 2H), 3.91 (s, 3H),3.63-3.80 (m, 3H), 3.49 (s, 2H), 2.95, 3.04 (2m, 2H), 2.70 (m, 2H),2.09, 2.18 (2m, 2H), 1.70 (m, 2H), 1.38, 1.49 (2 m, 2H) 108 1 Example 1 10.63 (br, 1H), 8.39 (s, 1H), 8.14 (d, J = 7.5 650.7 Example 64 Hz, 1H),7.88 (d, J = 9.0 Hz, 1H), 7.35-7.42 [M + H]⁺ (m, 3H), 7.25 (dd, J = 2.8,9.0 Hz, 1H), 7.18 (d, J = 2.8 Hz, 1H), 5.68 (m, 1H), 4.02 (q, J = 9.5Hz, 2H), 3.91 (s, 3H), 3.75 (m, 2H), 3.55-3.72 (m, 5H), 3.48 (s, 2H),2.94, 3.05 (2 m, 2H), 2.65 (m, 2H), 2.09, 2.18 (2m, 2H), 1.70 (m, 2H),1.38, 1.49 (2m, 2H) 109 1 Example 1  10.63 (br, 1H), 8.41 (s, 1H), 8.16(d, J = 7.7 606.7 Example 64 Hz, 1H), 7.89 (d, J = 9.0 Hz, 1H),7.33-7.44 [M + H]⁺ (m, 3H), 7.26 (dd, J = 2.8, 9.0 Hz, 1H), 7.18 (d, J =2.8 Hz, 1H), 5.68 (m, 1H), 4.15 (m, 2H), 3.97 (m, 2H), 3.91 (s, 3H),3.71 (m, 1 H), 3.48 (s, 2H), 2.94, 3.05 (2 m, 2H), 2.65 (m, 2H), 2.09,2.18 (2 m, 2H), 1.70 (m, 2H), 1.38, 1.49 (2 m, 2H) 110 1 Example 1  8.40(s, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.20- 449.3 Example 9  7.33 (m, 6H),4.52 (t, J = 5.9 Hz, 2H), 3.92 (s, [M + H]⁺ 3H), 3.80 (s, 2H), 2.90 (m,2H), 2.75 (t, J = 5.9 Hz, 2H), 2.45 (m, 1H), 2.06 (m, 2H), 1.82 (m, 2H),1.16-1.30 (m, 11H) 111 1 Example 1  10.92 (s, 1H), 8.40 (m, 2H), 7.89(d, J = 9.0 562.3 Hz, 1H), 7.73 (s, 1H), 7.25 (m, 2H), 6.99 (s, [M + H]⁺1H), 4.55 (t, J = 5.7 Hz, 2H), 3.94 (s, 3H), 3.71 (m, 1H), 3.47 (s, 2H),2.96 (m, 2H), 2.79 (t, J = 5.7 Hz, 2H), 2.17 (m, 2H), 1.77 (m, 2H),1.40- 1.50 (m, 2H) 112 1 Example 1  8.42 (s, 1H), 8.35 (d, J = 7.7 Hz, 1H), 8.11 (d, 469.3 J = 0.5 Hz, 1H), 7.89 (d, J = 9.0 Hz, 1H), 7.83 [M +H]⁺ (d, J = 5.3 Hz, 1H), 7.48 (dd, J = 0.5, 5.3 Hz, 1H), 7.26 (m, 2H),4.57 (t, J = 5.8 Hz, 2H), 3.94 (s, 3H), 3.75 (m, 1H), 3.02 (m, 2H), 2.81(t, J = 5.8 Hz, 2H), 2.18 (m, 2H), 1.81 (m, 2H), 1.50-1.62 (m, 2H) 113 2Example 29 — 437.5 [M + H]⁺ 114 2 Example 29 — 473.2 [M + H]⁺ 115 2Example 29 9.13 (d, J = 2.0 Hz, 1H), 8.87 (d, J = 2.0 Hz, 491.4 1H),7.99 (d, J = 8.8 Hz, 1H), 7.68 (m, 2H), [M + H]⁺ 7.53 (dd, J = 2.8, 8.8Hz, 1H), 7.46 (d, J = 12.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 4.15 (d, J= 6.4 Hz, 2H), 3.90 (s, 3H), 3.82 (s, 2H), 2.31 (m, 1H), 1.83-1.95 (m,4H), 1.65-1.80 (m, 1H), 1.07 (m, 4H) 116 2 Example 29 9.14 (d, J = 2.0Hz, 1H), 8.87 (d, J = 2.0 Hz, 431.3 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.64(d, J = 2.8 [M + H]⁺ Hz, 1H), 7.48 (dd, J = 2.8, 9.2 Hz, 1H), 7.38 (m,2H), 7.29 (m, 2H), 7.19 (t, J = 7.2 Hz, 1H), 6.50 (d, J = 16.4 Hz, 1H),6.29-6.34 (m, 1H), 4.17 (d, J = 6.4 Hz, 2H), 3.90 (s, 3H), 3.38 (m, 2H),2.39 (m, 1H), 1.81-1.94 (m, 4H), 1.73 (m, 1H), 1.07 (m, 4H) 117 2Example 29 9.13 (d, J = 2.0 Hz, 1H), 8.88 (d, J = 2.0 Hz, 419.2 1H),8.00 (d, J = 9.2 Hz, 1H), 7.63 (d, J = 2.4 [M + H]⁺ Hz, 1H), 7.55 (dd, J= 2.8, 9.2 Hz, 1H), 7.25 (m, 2H), 7.14 (m, 2H), 4.17 (d, J = 6.8 Hz,2H), 3.90 (s, 3H), 3.82 (m, 2H), 2.48 (m, 1H), 2.27 (s, 3H), 1.85-2.01(m, 4H), 1.75 (m, 1H), 1.07- 1.19 (m, 4H) 118 2 Example 29 — 461.1 [M +H]⁺ 119 2 Example 29 9.13 (d, J = 1.6 Hz, 1H), 8.86 (d, J = 1.6 Hz,455.3 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.83 (m, 4H), [M + H]⁺ 7.63 (d, J =2.8 Hz, 1H), 7.42-7.54 (m, 4H), 4.15 (d, J = 6.8 Hz, 2H), 3.90 (s, 3H),2.39 (m, 1H), 1.83-2.00 (m, 4H), 1.70 (m, 1H), 1.05- 1.12 (m, 4H) 120 2Example 29 9.14 (d, J = 2.0 Hz, 1H), 8.87 (d, J = 2.0 Hz, 433.3 1H),7.99 (d, J = 9.2 Hz, 1H), 7.64 (s, 1H), [M + H]⁺ 7.53 (dd, J = 2.8, 9.2Hz, 1H), 7.14-7.27 (m, 5H), 4.17 (d, J = 6.8 Hz, 2H), 3.90 (s, 3H), 2.58(m, 4H), 2.38 (m, 1H), 1.83-1.90 (m, 4H), 1.69 (m, 3H), 1.02-1.12 (m,4H) 121 2 Example 29 9.29 (d, J = 2.0 Hz, 1H), 8.72 (d, J = 2.0 Hz,445.2 1H), 8.04 (d, J = 9.6 Hz, 1H), 7.61 (s, 1H), [M + H]⁺ 7.59 (d, J =11.2 Hz, 1H), 7.46 (m, 2H), 7.29 (s, 1H), 7.17 (s, 1H), 6.74 (s, 1H),4.22 (d, J = 6.8 Hz, 2H), 3.95 (s, 3H), 3.93 (s, 2H), 2.57 (m, 1H),1.93-2.05 (m, 4H), 1.80-1.88 (m, 1H), 1.13-1.25 (m, 4H) 122 3 Example 358.62 (s, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.90 (d, 496.3 J = 9.1 Hz, 1H),7.35 (dd, J = 2.8, 9.1 Hz, 1H), [M + H]⁺ 7.28 (d, J = 2.8 Hz, 1H), 7.00(d, J = 1.6 Hz, 1H), 6.93 (m, 2H), 6.19 (br, 1H), 3.94 (s, 3H), 3.73 (m,1H), 3.48 (m, 4H), 3.00 (m, 4H), 2.72 (t, J = 6.8 Hz, 2H), 2.14 (m, 2H),1.76 (m, 2H), 1.58 (m, 2H) 123 1 Example 1  8.40 (s, 1H), 7.89 (d, J =9.0 Hz, 1H), 7.25 (d, 437.3 Example 9  J = 9.0 Hz, 1H), 7.22 (s, 1H),6.91 (s, 1H), [M + H]⁺ 6.78 (m, 2H), 5.97 (s, 2H), 4.52 (t, J = 5.6 Hz,2H), 3.92 (s, 3H), 3.61 (s, 2H), 2.88 (m, 2H), 2.74 (t, J = 5.6 Hz, 2H),2.32 (m, 1H), 2.02 (m, 2H), 1.76 (m, 2H), 1.24 (m, 2H)

Anti-Microbial Activity Assay.

The antibacterial activity of compounds is determined by the minimalinhibitory concentration (MIC) method. MICs for all bacteria exceptpneumococci and Haemophilus influenzae are obtained by brothmicrodilution with cation-adjusted Mueller-Hinton broth (CAMHB; BBL),according to CLSI guidelines (National Committee for Clinical LaboratoryStandards. 2003. Methods for dilution antimicrobial susceptibility testsfor bacteria that grow aerobically, 5^(th) ed.; approved standard M7-A6.National Committee for Clinical Laboratory Standards, Wayne, Pa.), withthe following modifications: (i) for pneumococci CAMHB is supplementedwith 5% (v/v) horse serum; (ii) for Haemophilus influenzae CAMHB issupplemented with 5% (v/v) Fildes enrichment (BBL) (Pankuch, G. A.,Hoellman, D. B., Lin, G., Bajaksouzian, S., Jacobs, M. R., andAppelbaum, P. C. 1998. Activity of HMR 3647 compared to those of fiveagents against Haemophilus influenzae and Moraxella catarrhalis by MICdetermination and time-kill assay. Antimicrob. Agents Chemother.42:3032-3034). Microtiter plates are incubated at 35° C. in ambient airfor 20 to 24 h, then inspected using an illuminated microtiter platereader fitted with a magnifying mirror (MIC 2000; Cooke LaboratoryProducts, Alexandria, Va.). Compounds of the present invention aretested against several bacteria strains comprising some Acinetobacterbaumannii, Enterococcus faecalis, Enterococcus faecitan, Escherichiacoli, Haemophilus influenzae, Klebsiella pneumoniae, Pseudomonasaeruginosa, Staphylococcus aureus, Staphylococcus epidermidis andStreptococcus pneumoniae. The MIC values (in mg/L) for the Examples 1 to56 are presented in Table 2.

TABLE 2 Staphylococcus Staphylococcus Streptococcus Escherichia aureusepidermidis pneumoniae coli Example/ ATCC29213 ATCC14990 ATCC49619UB1005 Compound MIC (mg/L) MIC (mg/L) MIC (mg/L) MIC (mg/L) 1 ≦2 ≦2 4 82 ≦2 ≦2 ≦2 >32 3 ≦2 ≦2 16 >32 4 ≦2 ≦2 >32 >32 5 ≦2 ≦2 ≦2 >32 6 ≦2 ≦24 >32 7 ≦2 >32 >32 >32 8 ≦2 4 16 16 9 ≦2 4 ≦2 4 10 4 8 8 >32 11 4 4 4 1612 4 4 16 ≧32 13 4 >32 >32 >32 14 ≦2 8 8 >32 15 ≦2 ≦2 8 4 16 ≦2 4 8 8 17≦2 4 16 >32 18 ≦2 ≦2 4 8 19 ≦2 ≦2 8 4 20 ≦2 ≦2 >32 >32 21 8 16 >32 ≧3222 4 4 32 16 23 4 4 16 16 24 8 8 16 4 25 8 16 16 8 26 4 16 8 >32 27 8 3232 16 28 ≦2 ≦2 >32 >32 29 ≦2 ≦2 4 >32 30 ≦2 4 >32 >32 31 ≦2 4 8 >32 32 816 32 >32 33 4 8 8 >32 34 8 >32 >32 >32 35 ≦2 ≦2 ≦2 >32 36 ≦2 ≦2 ≦2 4 37≦2 ≦2 ≦2 ≦2 38 ≦2 ≦2 ≦2 16 39 ≦2 ≦2 ≦2 ≧32 40 ≦2 ≦2 ≦2 ≦2 41 ≦2 ≦2 ≦2 842 ≦2 ≦2 ≦2 8 43 ≦2 ≦2 ≦2 16 44 ≦2 ≦2 4 4 45 ≦2 ≦2 ≦2 ≦2 46 ≦2 ≦2 ≦2 ≦247 ≦2 ≦2 ≦2 32 48 ≦2 ≦2 ≦2 ≦2 49 ≦2 ≦2 ≦2 4 50 ≦2 ≦2 ≦2 4 51 ≦2 ≦2 4 452 ≦2 ≦2 ≦2 16 53 ≦2 ≦2 ≦2 4 54 ≦2 ≦2 4 4 55 ≦2 ≦2 ≦2 16 56 ≦2 4 16 4The other described example compounds have a MIC for Staphylococcusaureus ATCC29213 of less or equal to 8 mg/L.

What is claimed is:
 1. A compound of formula I

wherein X1, X3; X4 and X6, each independently of the others, representsa nitrogen atom or CR2, with the proviso that at least one of X1, X3; X4and X6 represents a nitrogen atom; X2 represents C—H, C—(C1-C6alkyl),C—(C1-C6alkoxy), C-halogen, C—COOH; X5 represents C—H or C—(C1-C6alkyl),C-halogen; R1 and R2, independently of one another, represent hydrogenor a substituent selected from hydroxy, halogen, carboxy, amino,C1-C6alkylamino, di(C1-C6alkyl)amino, mercapto, cyano, nitro,C1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio, C1-C6alkylaminocarbonyloxy,C2-C6alkenyl, C2-C6alkynyl, C1-C6alkylcarbonyloxy,C1-C6alkylsulfonyloxy, C1-C6heteroalkylcarbonyloxy,C5-C6heterocyclylcarbonyloxy, C1-C6heteroalkyl, C1-C6heteroalkoxy,wherein heteroalkyl, heteroalkoxy groups or heterocyclyl comprise 1, 2or 3 heteroatoms selected from nitrogen, oxygen and sulphur, in whichsubstituents the alkyl moieties are unsubstituted or further substitutedby halogeno, cyano, hydroxy, C1-C4alkoxy, C1-C4alkylcarbonyl,C1-C4alkoxycarbonyl, unsubstituted or substituted phenoxy orphenylcarbonyl, unsubstituted or substituted C5-C6heterocyclyl orcarboxy; A1 represents a divalent group of one of the formulae—O—(CH₂)_(m)—(CH₂)—, —S—(CH₂)_(m)—(CH₂)— or —(C═O)O—(CH₂)_(m)—(CH₂)—,wherein the (CH₂)_(m) moiety is optionally substituted by C1-C4alkyl,C2-C4alkenyl, C3-C6cycloalkyl, C3-C6cycloalkylmethyl, morpholinomethyl,halogen, carboxy, hydroxy, C1-C4alkoxy; C1-C4alkoxyC1-C4alkyl,C1-C4alkoxy(C1-C4alkylenoxy)C1-C4alkyl, benzyloxyC1-C4alkyl, amino,mono- or di-(C1-C4alkyl)amino or acylamino, in which substituents thealkyl moieties can be further substituted by 1 or more fluoro atoms m is0, 1 or 2, provided that the number of atoms in the direct chain betweenthe two terminal valencies of A1 is at least 3, which group A1 is linkedto A2 via the terminal (CH₂)-moiety; A2 is a group selected fromC3-C8cycloalkylene; saturated and unsaturated 4 to 8-memberedheterocyclodiyl with 1, 2 or 3 heteroatoms selected from nitrogen,oxygen and sulphur, which group A2 is unsubstituted or substituted; R4represents hydrogen or C1-C4alkyl; A3 represents C1-C4alkylene,C2-C4alkenylene, >C═O, —C(O)C1-C3alkylene-, —C(═O)NH—, or a groupselected from —C₂H₄NH—, —C₂H₄O—, and —C₂H₄S— being linked to theadjacent NR4-group via the carbon atom; and G represents benzo orpyrido[1,4]oxazine which are unsubstituted or substituted by one or moresubstituents selected from the group consisting of alkyl, fluorine,chlorine, bromine or iodine, carboxy, alkoxy, NH₂, mono- ordi(C1-C4alkyl)amino, OH, cyano and NO₂, ═O, SH, ═S and ═NH and n is 0, 1or 2; or a pharmaceutically acceptable salt, a hydrate or solvatethereof.
 2. The compound of claim 1, wherein either X1 alone, X3 alone,X4 alone or X6 alone or either X3 and X1 or X3 and X6 or X1 and X4represent nitrogen.
 3. The compound of claim 1, wherein R1 is selectedfrom hydrogen, hydroxy, mercapto, cyano, nitro, C1-C6alkylsulfonyloxy,C1-C6alkylcarbonyloxy, C1-C6heteroalkylcarbonyloxy,C5-C6heteroarylcarbonyloxy and, more preferably from halogen, inparticular fluoro, and C1-C6alkoxy, preferably C1-C4alkoxy, inparticular methoxy.
 4. The compound of claim 1, wherein A2 represents agroup selected from C5-C6cycloalkylene and saturated or unsaturated 4 to6-membered heterocyclodiyl with one or two nitrogen atoms as theheteroatom(s), in particular unsubstituted C5-C6cycloalkylene andsaturated 4 to 6-membered heterocyclodiyl with one nitrogen atom as theheteroatom.
 5. The compound of claim 4 wherein A2 is selected from:

wherein * indicates the bond to the (CH₂)_(n) group in formula (I). 6.The compounds of claim 1, wherein G is a group of formula:


7. The compound of claim 1 wherein A1 represents —O—(CH₂)_(m)—(CH₂)— or—S—(CH₂)_(m)—(CH₂)— and m is as claimed in claim
 1. 8. The compound ofclaim 7 wherein m is
 1. 9. The compound of claim 1 wherein n is 0 or 1.10. The compound of claim 6 wherein X3 and X6 or X3 and X1 are nitrogen.11. The compound of claim 1 wherein R2 is selected from hydrogen,hydroxy, halogen, C1-C6alkyl, C1-C6alkoxy, carboxy.
 12. The compound ofclaim 4 or 5 wherein A2 is unsubstituted or substituted with a groupselected from hydroxy, C1-C4alkyl and carboxy.
 13. The compound of claim8 wherein (CH₂)_(m) is unsubstituted or substituted with groups selectedfrom C1-C6alkyl and C1-C6alkenyl.
 14. A pharmaceutical compositioncomprising a compound of claim 1 or a pharmaceutically acceptable salt,a hydrate or a solvate thereof.
 15. The compound of formula I accordingto claim 1, selected from the group consisting of the compounds:3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxylic acid{trans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexyl}-amide,3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid{trans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexyl}-amide,6-[({1-[3-(7-methoxy-quinoxalin-2-yloxy)-propyl]-piperidin-4-ylmethyl}-amino)-methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one,6-methoxy-[1,5]naphthyridine-3-carboxylic acidtrans-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbonyl)-amino]-cyclohexylmethylester, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide,and6-({1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amino)-methyl)-4H-benzo[1,4]oxazin-3-one,6-({1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one,or a pharmaceutically acceptable salt, a hydrate or solvate thereof. 16.The compound of formula I according to claim 1, selected from the groupconsisting of the compounds:6-[({1-[3-(7-methoxy-quinoxalin-2-yloxy)-propyl]-piperidin-4-ylmethyl}-amino)-methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one,3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide,6-({1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amino)-methyl)-4H-benzo[1,4]oxazin-3-one,and6-({1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one,or a pharmaceutically acceptable salt, a hydrate or solvate thereof. 17.The compound of formula I according to claim 1, selected from the groupconsisting of the compounds:6-[({1-[3-(7-methoxy-quinoxalin-2-yloxy)-propyl]-piperidin-4-ylmethyl}-amino)-methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one,3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide,6-({1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amino)-methyl)-4H-benzo[1,4]oxazin-3-one,and6-({1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one,or a pharmaceutically acceptable salt, a hydrate or solvate thereof. 18.The pharmaceutical composition of claim 14 further comprising apharmaceutically acceptable carrier.
 19. A process for the preparationof a compound of formula I as claimed in claim 1, wherein a compound ofthe formula II

is reacted with a compound of formula IIIG-A3b-L0  (III): in which formulae X1, X2, X3, X4, X5, X6, R1, A2, G,R4, m and n are as in formula I, A represents a group selected from —O—;—S—; and —C(═O)O—, the —C(═O)O— group being linked to the adjacent(CH₂)_(m) group via the oxygen atom, L0 is selected from —CH₂Y, —CHO,—COOH and —COCl, Y is a leaving group, in particular methylsulfonyl,tolylsulfonyl, trifluoromethylsulfonyl or halogen; A3b is absent orrepresents C1-C3alkylene, C1-C3alkenylene or a group selected from—CH₂NH—, —CH₂O—, and —CH₂S—, said group being linked to G via thenitrogen, oxygen or sulfur atom.
 20. A process for the preparation of acompound of formula I as claimed in claim 1, wherein a compound of theformula IV

is reacted with a compound of formula V

in which formulae X1, X2, X3, X4, X5, X6, R1, A2, R4, m and n are as informula I, L1 is C(═O)OH or a corresponding acid halide or otherwiseactivated acyl derivative, anhydride or mixed anhydride, OH, SH, Br, Clor a group OSO₂R in which R is CH₃, CF₃, or tolyl, and L2 is a halogenatom, SH, OH or a group OSO₂R in which R is CH₃, CF₃, or tolyl, and L1and L2 are selected such that the reaction results in the formation of acompound of formula VIII

wherein A represents a group selected from —O—; —S—; and —C(═O)O—, the—C(═O)O— group being linked to the adjacent (CH₂)_(m) group via theoxygen atom, E is an amino protecting group or a group of formula -A3-G,wherein A3 and G have the same meaning as in formula I, and when E is aprotecting group, said protecting group is removed and the deprotectedintermediate is reacted with a compound of formula IIIG-A3b-L0  (III): wherein G is as defined above, A3b is absent orrepresents C1-C3alkylene or a group selected from —CH₂NH—, —CH₂O—, and—CH₂S—, said group being linked to G via the nitrogen, oxygen or sulfuratom, L0 is selected from —CH₂Y, —CHO, —COOH and —COCl, and Y is aleaving group, in particular methylsulfonyl, tolylsulfonyl,trifluoromethylsulfonyl or halogen.
 21. A process for the preparation ofa compound of formula I as claimed in claim 1, wherein a compound offormula VI

is reacted with a compound of formula VII

wherein in the formulae (VI) and (VII) X1, X2, X3, X4, X5, X6, R1, R4, mand n are as in formula I, A represents a group selected from —O—; —S—;and —C(═O)O—, the —C(═O)O— group being linked to the adjacent (CH₂)_(m)group via the oxygen atom, A2 is an unsubstituted or substituted,saturated or unsaturated 4 to 8-membered heterocyclodiyl group with 1, 2or 3 heteroatoms selected from nitrogen, oxygen and sulphur, at leastone of which heteroatoms is nitrogen atom and H^([-N]) represents ahydrogen atom bound to a nitrogen ring atom of A2, L3 is —CHO, and E isan amino protecting group or a group of formula -A3-G, wherein A3 and Ghave the same meaning as in formula I, and wherein when E is aprotecting group, said protecting group is removed and the deprotectedintermediate is reacted with a compound of formula IIIG-A3b-L0  (III) wherein G is as defined above, A3b is absent orrepresents C1-C3alkylene or a group selected from —CH₂NH—, —CH₂O—, and—CH₂S—, said group being linked to G via the nitrogen, oxygen or sulfuratom, L0 is selected from —CH₂Y, —CHO, —COOH and —COCl and Y is aleaving group, in particular methylsulfonyl, tolylsulfonyl,trifluoromethylsulfonyl or halogen.
 22. The compound of claim 1 which is3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide,or a pharmaceutically acceptable salt, a hydrate or solvate thereof. 23.The compound of claim 1 which is6-({1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amino)-methyl)-4H-benzo[1,4]oxazin-3-one,or a pharmaceutically acceptable salt, a hydrate or solvate thereof. 24.The compound of claim 1 which is6-({1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one,or a pharmaceutically acceptable salt, a hydrate or solvate thereof. 25.The compound of claim 1 which is3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxylic acid{1-[2-(6-methoxy-[1,5]naphthyridin-3-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide,or a pharmaceutically acceptable salt, a hydrate or solvate thereof. 26.The compound of claim 1 which is3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxylic acid{1-[2-(6-methoxy-[1,5]naphthyridin-3-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide,or a pharmaceutically acceptable salt, a hydrate or solvate thereof.